胃肠外科 · 本周文献汇编

Early-stage colorectal cancer (CRC) with confirmed microsatellite instability generally has a favorable prognosis associated with pronounced immune infiltration. However, some patients still develop metastases. The underlying mechanisms, particularly those related to the tumor immune microenvironment, remain incompletely understood. The study included tissue samples from 217 patients with dMMR/MSI-H CRC, comprising 89 stage III/IV and 128 stage I/II cases. Tissue microarrays and immunohistochemical analyzes were performed for all cases. We evaluated immune markers identifying T cells, B cells, dendritic cells, natural killer cells, macrophages, immunosuppressive markers, and immune checkpoint targets in epithelial and stromal compartments, and additionally performed a cohort-derived immune infiltration score (IIS). The survival analysis assessed the prognostic impact of immune markers stratified by tumor stage. Stage I/II dMMR/MSI-H CRCs showed significantly higher CD3⁺ T-cell and natural killer cell levels, higher IIS metrics across all regions, and higher CD4⁺ T helper cell levels in the stroma. Stage III/IV cases exhibited increased epithelial expression of indoleamine 2,3-dioxygenase 1. Given the limited number of stage IV patients, an additional stage III vs. stage I/II comparison was performed, revealing that these immune differences were already evident at the level of nodal progression. In addition, CD3⁺, CD4⁺, and CD8⁺ T cells and the IIS showed varying prognostic associations across tumor stages. These findings suggest that the overall immunogenicity and prognostic relevance of immune markers in dMMR/MSI-H CRC depend on tumor stage. Immune profiling could be used for early-stage patient stratification and also suggests the potential benefit of early immunotherapeutic intervention.

The survival impact of American College of Surgeons Commission on Cancer (CoC) accreditation on colorectal cancer care remains uncertain, particularly when assessed using both outcome-based and process-based quality frameworks. Hospitals were evaluated using two approaches: an Outcome Method based on 5-year mortality hazard and a Criteria Method based on adherence to evidence-based quality metrics. Data were derived from the National Cancer Database and Centers for Medicare & Medicaid Services. Hospitals were compared by performance tier and CoC accreditation status. Among 1,227 CoC-accredited hospitals, the Outcome Method classified 168 (14%) high-, 861 (70%) medium-, and 198 (16%) low-tier hospitals. Compared with medium-tier hospitals, high-tier hospitals demonstrated lower 5-year mortality hazard (HR 0.63, 95%CI 0.6-0.66), whereas low-tier hospitals had higher hazard (HR 1.51, 95%CI 1.44-1.58). The Criteria Method identified 194 (16%) high-performing and 1,033 (84%) average-performing hospitals; high-performing hospitals had reduced 5-year mortality (HR 0.86, 95%CI 0.81-0.90). Compared with 2,107 non-CoC hospitals, treatment at CoC-accredited hospitals was associated with reduced 1-year mortality using both methods: Outcome Method-high-tier HR 0.81 (95%CI 0.76-0.87), medium-tier HR 0.91 (95%CI 0.87-0.95); Criteria Method-high-performing HR 0.83 (95%CI 0.77-0.88), average-performing HR 0.92 (95%CI 0.88-0.96). Higher-quality colorectal cancer care, defined by either mortality-based or criteria-based methodologies, is associated with improved survival. CoC accreditation is consistently associated with reduced short-term mortality, supporting its role as a systems-level marker of quality.

Numerous studies have linked gut microbiome alterations to colorectal cancer (CRC), but limited sample sizes and study heterogeneity have hampered cross-study comparisons and subgroup analyses. Here, we present a comprehensive single-disease gut microbiome meta-analysis based on consistently re-computed and re-analyzed shotgun and amplicon sequencing profiles (n = 6,779 samples, 27 studies). Association and machine-learning analyses delineate CRC microbiome signatures, which are robustly generalizable across studies and sequencing approaches and nearly identical between early- and late-onset cases. Meta-analysis of the tumor-resident microbiome reveals characteristic tumor-enriched microbes in concordance with fecal signatures that are clearly detectable in early-stage tumors, although their detection in feces becomes moderately higher in late-stage and distal tumors, possibly due to dilution effects in stool. The unified fecal CRC signature inversely associates with dietary fiber intake and is modifiable by dietary interventions. Finally, genome-resolved functional analysis reveals variation in virulence factor carriage and geographic enrichment across Fusobacterium subspecies.

Fusobacterium nucleatum (Fn) has been implicated in the progression of colorectal cancer (CRC), immune modulation, and resistance to systemic therapies. However, its role as a predictive biomarker of treatment response remains unclear. We conducted a systematic review to evaluate the association between Fn and oncologic treatment outcomes in CRC. This systematic review was performed according to the PRISMA 2020 guidelines and registered in PROSPERO (CRD420261327958). MEDLINE, Scopus, and CENTRAL were searched through March 2026. Eligible studies included adult CRC patients with Fn assessment performed before or during treatment and reporting treatment-related outcomes. Primary endpoints included pathological complete response (pCR), tumour regression grade (TRG), and objective response rate (ORR). Secondary endpoints included disease-free survival (DFS), relapse-free survival (RFS), progression-free survival (PFS), and overall survival (OS). Eleven studies including 1571 patients, were analysed. In locally advanced rectal cancer, four of five studies indicated that higher pre-treatment Fn abundance was associated with poorer pathological response to neoadjuvant chemoradiotherapy. Persistent Fn positivity after treatment was linked to an increased relapse risk. In metastatic CRC receiving immunotherapy, two studies reported enrichment of Fn in non-responders, while one study observed improved outcomes in Fn-positive tumours treated with PD-L1 blockade. In chemotherapy-treated metastatic CRC, Fn abundance was significantly higher in patients with progressive disease. Overall, the quality of evidence was rated low to very low. Fn appears to be associated with treatment resistance across multiple CRC settings and may represent a promising biomarker and therapeutic target. Prospective biomarker-driven studies are warranted.

Limited data availability and privacy constraints hinder the development of robust survival prediction models for personalized treatment. Synthetic data offers a promising solution, preserving the statistical properties of real clinical data. This study aimed to quantitatively assess the feasibility of using synthetic data for survival prediction by evaluating model transfer performance to real-world hospital data, with a focus on model transfer strategies. We developed and validated colorectal cancer survival prediction models using the National Cancer Data Center (NCDC) synthetic data (30,683 patients from 3 Korean institutions) for pretraining and real hospital data (2170 patients from Hwasun Jeonnam University Hospital) for external validation. We evaluated 3 model transfer strategies-domain adaptation, zero-shot, and ensemble-using extreme gradient boosting (XGBoost) and light gradient boosting machine (LightGBM). In total, 48 model configurations were tested, defined by the combination of algorithms (LightGBM and XGBoost), sampling technique (no-sampling, random undersampling [RUS], and synthetic minority oversampling technique combined with edited nearest neighbors [SMOTEENN]), model type (baseline, domain adaptation, zero-shot, and ensemble), and optimization objective (area under the precision-recall curve [AUPRC] and F1). The outcome was 7-year overall survival, evaluated using the AUPRC and Brier scores. Performance was compared against a hospital-only baseline using absolute values and deltas (ΔAUPRC and ΔBrier). Differences and corresponding 95% CIs were estimated on the held-out test set using 2000 bootstrap samples. Zero-shot application reduced the AUPRC in most settings, and any marginal improvements observed in the remaining settings were not statistically significant. In contrast, the domain adaptation model improved AUPRC in 8/12 combinations, with 4 statistically significant gains; the best setting (XGBoost+RUS+F1 optimization) achieved AUPRC=0.5391 (Δ+0.1474; P<.001). The soft ensemble increased AUPRC in 7/12 combinations, with 3 statistically significant gains; the best setting (XGBoost+RUS+AUPRC optimization) achieved AUPRC=0.5060 (Δ+0.1258, P=.002). For calibration, Brier scores improved in most domain adaptation and ensemble combinations, with a substantial proportion reaching statistical significance. When domain adaptation using local hospital data was applied, the model pretrained on synthetic data exhibited similar performance to the hospital-only baseline across various settings. This study demonstrates the methodological utility of a model transfer approach using NCDC synthetic data in a setting with limited data sharing. At the same time, it clarifies that while synthetic data can serve as a complement to local clinical data, it is not a substitute for real-world clinical models.

The primary treatment for non-metastatic colorectal cancer is surgical resection. Despite the use of neoadjuvant and/or adjuvant chemoradiation, up to 30% of patients undergoing surgery for colorectal cancer will develop a postoperative recurrence. Why patients develop postoperative tumors despite all known cancer being resected at the time of surgery is largely unknown, and novel biomarkers that can predict the development of recurrence are lacking. Here, we report a unique bacterial signature present in the gut during the perioperative period that is strongly associated with the development of postoperative tumors. By studying patients undergoing resection for colorectal cancer, we demonstrate that the gut microbiome on the day of surgery is enriched with collagenase-producing bacteria in patients who later develop a recurrence. This bacterial community demonstrated enhanced antimicrobial resistance, was not eradicated by the standardized perioperative bowel preparation, and could promote cancer cell migration and invasion. Our study establishes that microbiota may contribute to postoperative colorectal cancer recurrence and serve as a prognostic biomarker for postoperative oncologic outcomes.

Colorectal cancer (CRC) is influenced by genetic, environmental, and dietary factors, with increasing evidence highlighting the role of the gut microbiota in its development. Probiotics, prebiotics, and fermented foods such as yogurt have been recognized for their ability to promote gut microbial balance and potentially reduce CRC risk. This study try to investigate the association between the consumption of these dietary components and CRC prevalence among adults aged 50 years and older. This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2020. Dietary intake was assessed using the Food Frequency Questionnaire and the 30-Day Dietary Supplement Use Questionnaire, while CRC history was based on self-reported diagnoses. Multivariable logistic regressions were applied, adjusting for demographic characteristics (age, sex, race/ethnicity, poverty income ratio, education), lifestyle factors (smoking status, total energy intake, red meat intake, total dietary fiber intake), and clinical variables (BMI, cardiovascular disease, chronic kidney disease, fasting plasma glucose, and serum albumin). The final analytic sample included 9405 participants, representing an estimated 37 million U.S. adults. After adjustment, consumption of probiotics, prebiotics, or yogurt was associated with approximately 50% lower odds of CRC (adjusted odds ratio = 0.50; 95% CI: 0.29-0.88). These findings indicate a potential protective association of these dietary components with CRC, likely mediated through modulation of the gut microbiota. While the cross-sectional design limits causal interpretation, the results support existing literature on the beneficial role of diet in cancer prevention. Further longitudinal studies are necessary to confirm these associations and inform public health strategies aimed at reducing CRC risk through targeted dietary interventions.

Adjuvant chemotherapy is the standard management approach for patients with stage II/III colon cancer; however, the effectiveness in older patients is still unclear. This study aimed to explore the efficacy of adjuvant chemotherapy and whether oxaliplatin-based chemotherapy has better oncological outcomes than capecitabine monotherapy in older patients with stage III or high-risk stage II colon cancer. We analyzed and compared oxaliplatin-based adjuvant chemotherapy with capecitabine monotherapy and non-adjuvant chemotherapy in 468 patients aged ≥70 years with stage III and high-risk stage II colon cancer, and a propensity score-matched analysis was conducted. The endpoints were overall survival (OS), cancer-specific survival (CSS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Multivariate analysis shows that adjuvant-treated stage III or high-risk stage II patients experienced a highly significant increase in OS (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.20-0.59, P <0.001) and CSS (HR: 0.39, 95% CI: 0.20-0.75, P = 0.005) compared with the control group without adjuvant chemotherapy. By contrast, no statistically significant difference was observed in either LRFS or DMFS (all P >0.05). The subgroup analysis suggested that no statistically significant benefits were observed between oxaliplatin-based adjuvant chemotherapy and capecitabine monotherapy, and no significant differences in oncological outcomes were detected with ≥6 months of therapy compared with 3-6 months (excluding 6 months) of therapy. Older patients with stage III or high-risk stage II colon cancer can benefit from adjuvant chemotherapy, and capecitabine monotherapy has non-inferior oncological outcomes compared with oxaliplatin-based regimens. ClinicalTrials.gov , NCT04074538.

Although vitamin D (VitD) exhibits anti-tumor activity in colorectal cancer (CRC) preclinically, its effects in the human tumor microenvironment (TME) remain unclear. We conducted a randomized, placebo-controlled trial of preoperative high-dose VitD supplementation in stage I-III colon cancer patients to assess its impact on the TME. Forty-two patients received either VitD3 (50,000 IU/day for 7 days, then 10,000 IU/day) or placebo before surgery. Spatial immune-profiling and assessment of VitD receptor (VDR) and CYP27B1 expression were performed on paired tumor samples from 24 patients. VitD significantly increased plasma 25-hydroxyvitamin D levels (P<0.001), increased CD3+CD8+ memory T cells (P=0.03), reduced CD3+CD4+FoxP3+ regulatory T cells (P=0.02) and spatially re-organized the TME, leading to greater T cell and tumor cell proximity. Post-treatment VDR expression was heterogeneous and decreased overall (P=0.02). Spatial transcriptomic profiling of post-treatment resections reflected predominantly repressive VDR activity. These findings support an immunomodulatory role for VitD, warranting further mechanistic investigation.

The prognosis for advanced colorectal cancer (CRC) remains poor, and 5-fluorouracil (5-FU)-based chemotherapy is the primary treatment option. Understanding the mechanisms that limit the effectiveness of this therapy is therefore clinically important. However, the molecular drivers of acquired chemotherapy resistance in advanced CRC are not fully understood. Here we show that expression of PDZ-LIM domain-containing protein 4 (PDLIM4) is significantly upregulated following neoadjuvant chemotherapy in patients with advanced CRC, and that its expression level is closely associated with patient prognosis. PDLIM4 promotes acquired resistance to 5-FU by enhancing the stemness, anti-apoptotic capacity, and drug efflux of colorectal cancer stem cells. Mechanistically, PDLIM4 facilitates the accumulation of sphingolipids, particularly sphingomyelin, and regulates the PI3K/Akt signaling pathway. These findings identify PDLIM4 as a potential biomarker and therapeutic target for overcoming chemoresistance in advanced colorectal cancer, opening new avenues for future treatment strategies.

This review explores how gut microbiota reshapes colorectal cancer (CRC) molecular landscape, driving initiation/progression via key mechanisms. Microbes/metabolites cause driver mutations (DNA damage, signaling interference) and alter epigenetics (DNA methylation, histone modifications, ncRNAs) to boost tumor cell proliferation/survival. Dysbiosis disrupts tumor immune microenvironment (TIME) by impairing immune cells and increasing immunosuppressive factors, fostering immune evasion.Integrating molecular biology, microbiology, and immunology, we show microbial changes are causal in oncogenesis, with species acting distinctly across tumor stages. These insights clarify CRC pathogenesis and support microbiota-based prevention, diagnosis, treatment. Targeting microbes/metabolites or signaling pathways could cut CRC risk, improve early detection, and boost therapy. The review highlights microbiota-targeted therapy's promise and guides future research/clinical translation.

The progression of colorectal cancer (CRC) is highly dependent on tumor angiogenesis, a process primarily regulated by hypoxia-inducible factor HIF-1α. This study focuses on the mechanistic role of protein arginine methyltransferase 6 (PRMT6) in CRC angiogenesis and reveals that PRMT6 is significantly overexpressed in CRC tissues, stabilizing HIF-1α via the autophagy-lysosome pathway. Specifically, PRMT6 catalyzes the asymmetric dimethylation of HIF-1α at arginine 463, which disrupts its interaction with the autophagy-related protein TAX1BP1, thereby preventing its degradation. In vivo experiments demonstrate that PRMT6 silencing reduces HIF-1α stability, decreases vascular endothelial growth factor A (VEGFA) expression, and markedly suppresses tumor angiogenesis and growth. This study identifies the PRMT6-HIF-1α axis as a novel therapeutic target for CRC and suggests that targeting this pathway may facilitate the development of precision anti-angiogenic therapies.

Metastasis is the principal cause of death from colorectal cancer (CRC), yet the cellular states that enable tumor dissemination remain poorly defined. Disseminated tumor cells (DTCs) are rare, transient, and clinically inaccessible, limiting mechanistic insight into their biology. Here we show that CRC cells transiently adopt a wound-healing program normally used by epidermal keratinocytes during tissue repair to enable metastatic dissemination. Using serial orthotopic transplantation of patient-derived organoids to model metastasis, we find that DTCs lose cancer stem cell features and instead express wound-inducible keratins, including KRT17, before metastatic outgrowth. This state is reversible, as cells reacquire primary tumor-like characteristics upon colonization of distant organs. Mechanistically, this transition is associated with reduced EZH2 activity and activation of YAP signaling. Clinically, KRT17⁺ cells localize to the invasive front of primary CRCs and are absent from adjacent normal tissue. These findings uncover unexpected lineage plasticity across distinct developmental origins and identify a transient, targetable state critical for metastatic progression.

HDAC3 is highly expressed in colorectal cancer (CRC) and associated with poor prognosis. This study reveals that HDAC3 deletion dually regulates chemokine expression through epigenetic mechanisms, promoting CD8⁺ T cell infiltration (via CXCL10) on one hand, while enhancing the recruitment of myeloid-derived suppressor cells (MDSCs) (via CXCL1/2/3/5) on the other. The latter, mediated through CXCR2 signaling, counteracts the intrinsic anti-tumor effect of HDAC3 deletion. We further demonstrate that combining a CXCR2 inhibitor effectively blocks MDSC infiltration and significantly enhances the immunotherapeutic efficacy mediated by HDAC3 deletion. This study systematically elucidates the "double-edged sword" role of HDAC3 in the CRC immune microenvironment and provides a theoretical and experimental basis for an HDAC3/CXCR2 dual-targeting therapeutic strategy.

5-Fluorouracil (5-FU) resistance continues to pose a considerable barrier in the postoperative management of advanced colorectal cancer (CRC). This study identified Naked cuticle homolog 1 (NKD1) as a key factor associated with 5-FU resistance in CRC based on sequencing data from the GEO and TCGA databases. Elevated NKD1 expression correlated with adverse clinicopathological features and poor patient survival. Functional assays revealed that NKD1 overexpression elevated the IC50 of 5-FU, promoted tumor cell proliferation, and attenuated apoptosis in both drug-treated and untreated settings. Additionally, NKD1 promoted CRC cell migration and invasion, regulated tumor stem cell markers. Mechanistically, NKD1 stabilizes DVL protein, regulates APC and FZD7, and fosters nuclear accumulation of β-catenin, initiating transcriptional programs downstream of Wnt signaling. Silencing NKD1 synergized with 5-FU to improve therapeutic efficacy in patient-derived organoid and xenograft models. These results establish NKD1 as a key regulator of CRC malignancy and chemoresistance via Wnt/β-catenin pathway activation, supporting its potential as a dual biomarker and therapeutic target in combination regimens.

KRAS-mutant colorectal cancer (CRC) exhibits an aggressive metastatic phenotype, largely driven by TGFβ-induced epithelial-mesenchymal transition (EMT). However, the downstream effectors mediating TGFβ-driven metastasis in this context remain incompletely defined. This study identifies interferon regulatory factor 2 (IRF2) as a key metastasis suppressor and direct transcriptional repression target of TGFβ-SMAD2/3 signaling. IRF2 expression is markedly downregulated at invasive tumor fronts, showing a significant inverse correlation with p-SMAD2 levels and advanced metastatic stage. Single-cell trajectory analysis reveals temporal IRF2 suppression precisely coinciding with TGFβ/EMT program activation during metastatic progression. Mechanistically, SMAD2/3 complexes directly bind the IRF2 promoter to mediate repression, and IRF2 overexpression effectively reverses TGFβ1-induced invasive phenotypes in vitro. Pharmacological TGFβR1 inhibition restores IRF2 expression, slowing tumor progression and extending survival in the KRAS-driven iKAP mouse model. Furthermore, IRF2 reconstitution potently inhibits CRC cell invasion and metastasis by transcriptionally repressing EMT-related genes and enhancing anti-tumor immunity, characterized by increased CD8+ T-cell infiltration and reduced regulatory T cells (Tregs). While active in various CRC contexts, the TGFβ-SMAD2/3-IRF2 axis is particularly critical in KRAS-mutant CRC, where IRF2 loss acts as a functional second hit to accelerate dissemination. These findings uncover a TGFβ-SMAD2/3-IRF2 axis governing EMT and metastatic dissemination, positioning IRF2 restoration as a promising therapeutic strategy for aggressive KRAS-mutant CRC.

Argininosuccinate synthetase 1 (ASS1) is a rate-limiting enzyme in arginine biosynthesis, and its stability is regulated by TRAF2-mediated ubiquitination. Here, we report OTUB2 as a major deubiquitinase to stabilize ASS1, resulting increased arginine biosynthesis in colorectal cancer (CRC) cells; OTUB2 expression is elevated in CRC tissue, and patients with high OTUB2 expression exhibit shorter overall survival. As such, ectopic expression of OTUB2 promotes growth of CRC cells and xenograted tumors and accelerates cell migration and lung metastasis. Moreover, arginine deprivation induces marked expression of OTUB2 in CRC cells; mechanistically, arginine deprivation can activate AMPK, which in turn phosphorylates DDIT3, resulting its disassociation from C/EBPα and subsequent translocation into the cytoplasm and leading to increased binding of C/EBPα to the proximal promoter region of OTUB2 gene. Together, these data uncover a signaling pathway constituted of AMPK- DDIT3-C/EBPα-OTUB2-ASS1 to sense arginine deficiency and stimulate a metabolic compensatory pathway to sustain arginine homeostasis in CRC cells.

Studies have highlighted the important roles of circRNAs in various cancers. However, their specific functions in the lymph node metastasis (LNM) of colorectal cancer (CRC) remain largely unclear. The Arraystar human circRNA microarray was used to identify circular RNAs (circRNAs) associated with LNM in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure circHELQ expression in CRC cell lines and tissue specimens. A series of in vitro and in vivo functional assays were subsequently conducted to investigate the role of circHELQ in LNM and CRC progression. Additionally, fluorescence in situ hybridization, dual-luciferase reporter assays, RNA pull-down, and Western blot experiments were carried out to elucidate the underlying regulatory mechanisms of circHELQ in CRC. Our results demonstrated that circHELQ expression was significantly upregulated in CRC and that its expression level was closely correlated with LNM. Gain- and loss-of-function experiments revealed that circHELQ promotes CRC progression and metastasis-including proliferation, migration, invasion, lymphatic vessel formation, and LNM-both in vitro and in vivo. Mechanistically, circHELQ acts as a competing endogenous RNA (ceRNA) that sponges miR-4793-3p, thereby alleviating its suppression of VEGFC. This circHELQ/miR-4793-3p/VEGFC axis drives LNM in CRC by upregulating VEGFC expression. Furthermore, we developed a cancer cell membrane-based siRNA delivery system (cMDS) targeting circHELQ, and these nanoparticles effectively suppressed CRC proliferation and LNM. CircHELQ drives CRC progression and LNM and is a candidate prognostic biomarker. Furthermore, its molecular function renders it a viable target for nanoparticle-based therapeutic strategies against CRC.

Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking. Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC. We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality. Western diet exacerbated the CRC phenotype in APC 1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (C. scindens/Extibacter muris) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta. This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.

Claudin-1 (CLDN1), a tight junction protein overexpressed and mis-localized in colorectal cancer (CRC), plays a critical role in tumor progression, stemness, and therapy resistance. Integrative analyses of bulk and single-cell transcriptomic datasets revealed that CLDN1 is enriched in stem-like CRC cells, increases during metastatic progression, and is associated with microsatellite stable disease. High CLDN1 expression correlates with epithelial-to-mesenchymal transition and activation of oncogenic pathways including AKT/mTOR, Myc, and NF-κB. Here, we evaluate the therapeutic efficacy of an investigational humanized monoclonal antibody (H3L3) directed against overexpressed non-junctional CLDN1 in preclinical models of CRC. In xenograft mouse models and patient-derived organoids (PDOs), CLDN1 mAb significantly reduced tumor growth in CLDN1-expressing tumors. Mechanistically, CLDN1 mAb disrupted CLDN1-mediated signaling, notably inhibiting the AKT/mTOR pathway. CRISPR-mediated CLDN1 knockout abolished H3L3 efficacy, confirming target specificity. Transcriptomic analysis of PDOs treated with H3L3 revealed broad suppression of stemness, oncogenic signaling, and hallmark cancer pathways. Single-cell analysis further demonstrated that targeting CLDN1 modulates cellular plasticity, driving stem-like tumor cells toward a more differentiated epithelial phenotype. Together, these findings establish anti-CLDN1 monoclonal antibodies as a promising therapeutic approach for CRC. The selective binding of CLDN1 mAb to tumor-associated exposed and overexpressed CLDN1, along with its capacity to inhibit key oncogenic pathways and reprogram cancer cell states including tumors with different mutations conferring resistance to standard of care, underscores its potential to improve treatment outcomes in patients with CLDN1-expressing CRC.

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs)-the dominant stromal component-actively shape cancer progression through exosome-mediated communication. Here, we identify hsa_circ_0003892 (circLDLR), a CAF-derived circRNA, as a key factor associated with poor prognosis in colorectal cancer (CRC). During interactions between CAFs and CRC cells, circLDLR is packaged into exosomes and transferred to tumor cells, where it enhances proliferation and metastasis primarily by reducing susceptibility to ferroptosis. Mechanistically, circLDLR stabilizes Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) by protecting it from ZNRF2-mediated ubiquitination and degradation. This stabilization promotes the O-GalNAcylation of Solute Carrier Family 7 Member 11 (SLC7A11) at Ser26, facilitating its membrane localization and thereby suppressing ferroptosis in CRC cells. Additionally, we demonstrate that the RNA-binding protein EIF4A3 facilitates circLDLR biogenesis within CAFs. Taken together, our study reveals that CAF-derived circLDLR confers ferroptosis resistance and promotes CRC progression via the GALNT14/SLC7A11 axis. Consequently, disrupting exosomal circLDLR transfer between CAFs and CRC cells may offer a promising therapeutic strategy for CRC. Schematic diagram of the mechanism by which CAF-derived circLDLR promotes CRC progression through ferroptosis regulation. In the tumor microenvironment, CAFs highly express circLDLR, whose biogenesis is facilitated by EIF4A3-mediated splicing of LDLR pre-mRNA. circLDLR is then packaged into exosomes and transferred to CRC cells. Within CRC cells, circLDLR specifically binds to GALNT14 and inhibits its ubiquitination and degradation mediated by ZNRF2, thereby enhancing GALNT14 protein stability. Stabilized GALNT14 promotes O-GalNAcylation of SLC7A11 at Ser26, facilitating its membrane localization and increasing cystine uptake. The elevated cystine metabolism enhances GSH production, thereby suppressing ferroptosis and driving CRC cell proliferation and progression.

Immunoassay methods such as enzyme-linked immunosorbent assay using antigen-antibody reactions have been applied to detect biomarker proteins in the case of various diseases (e.g., cancer). However, these methods comprise several-hour-long pre-treatment processes (incubation and washing) before detection, and their sensitivity is limited by the affinity of protein and antibody sets. Here, we demonstrate the rapid and highly sensitive analysis of a cancer biomarker at several hundreds of attograms using a microflow-type light-induced acceleration system (MF-LAC-SYS) to enhance the reaction between the multiple antibodies and glycoprotein (CEACAM-5) from human plasma containing multiple impurities with the help of theoretical analysis. Adjusting the surface charge of the antibody-modified beads and buffer solution components, we could detect pg mL-1 levels of CEACAM-5 at high sensitivity under a laser beam irradiation of several hundred mW for several minutes at a defocused condition equivalent to the microchannel width. Specifically, we discovered the existence of nanoscale CEACAM-5 aggregates related to the sensitivity of the MF-LAC-SYS, using dynamic light scattering and electron microscopy. The results will potentially pave the way for a platform using unconventional immunoassays for liquid biopsy and blood proteomics.

Targeting topoisomerase I (Topo I) remains a pivotal strategy for the treatment of colorectal cancer (CRC). In this study, we rationally designed and synthesized a series of flavonolactam derivatives and systematically evaluated their biological activities and mechanisms of action. Among these, compounds NL-26 and NL-28 exhibited potent inhibitory effects on Topo I activity, arresting the cell cycle at the G2/M phase and inducing apoptosis to suppress tumor cell proliferation. Notably, NL-26 displayed the most potent Topo I inhibitory activity, which was comparable to that of the reference inhibitor camptothecin (CPT). In vivo pharmacokinetic studies revealed that NL-26 possesses a desirable profile, characterized by an AUC0-t of 1979.7 h ng/mL and a t1/2 of 3.7 h. Furthermore, NL-26 demonstrated robust antitumor efficacy in HCT116 xenograft models, achieving a tumor growth inhibition (TGI) of 55.1%. Collectively, these findings identify NL-26 as a promising lead compound and validate the flavonolactam scaffold as a privileged template for the development of next-generation Topo I-targeting therapeutics.

This commentary discusses the phase I study of fecal microbiota transplantation plus anti-programmed cell death protein 1 therapy in refractory microsatellite-stable gastric cancer. We suggest that this strategy should be treated as a pharmacomicrobiomic intervention rather than only as an immunotherapy combination. Evidence from fecal microbiota transplantation trials and microbiome immunotherapy studies indicates that antibiotics, proton pump inhibitors, corticosteroids and other microbiome-modifying exposures may affect donor strain engraftment, immune activation, response assessment and safety. In China and other Asian settings, where acid suppression, Helicobacter pylori history, perioperative antibiotic use and nutritional interventions are common, standardized concomitant medication reporting would make future studies more interpretable and transferable.

Organoid technology holds great potential and hope for personalized treatment in gastric cancer (GC). To date, clinicians' views on this technology for precision oncology have not been reported despite these insights being invaluable to understanding how organoids may be effectively integrated into clinical practice. Hence, we explored clinicians' knowledge and perception of organoid research and its potential clinical utility in GC treatment. Clinicians believed that organoids would be most useful for guiding adjuvant treatment in patients who fail neoadjuvant therapy and emphasized the importance of obtaining results within 4-6 weeks of surgical resection. Clinicians also expressed concerns and suggestions related to current research methodologies and highlighted the ethical and political aspects of organoid-guided personalized medicine. Overall, most clinicians perceived the value in the use of organoids to guide personalized treatment in GC and provided important insights into how this approach could be best implemented in clinical practice in the future.

The benefit of endoscopy for non-cardia gastric cancer (GC) prevention lacks evidence from randomized controlled trials (RCTs). This study aimed to evaluate the effect of endoscopic screening for non-cardia GC through an RCT. We conducted a cluster RCT in rural Hua County, northern China (ClinicalTrials.gov, NCT01688908). A total of 668 villages were randomly selected and assigned to either undergo upper gastrointestinal endoscopic screening (screening group) or no screening (control group). Permanent residents aged 45-69 years were enrolled from January 2012 to September 2016. Non-cardia GC mortality between the two groups was compared in intention-to-treat, per-protocol, and subgroup analyses. Poisson regression fitted with generalized estimating equations was used, adjusting for baseline characteristics and accounting for village clustering. The study enrolled 17,104 participants in the screening group, of whom 15,165 (88.7%) underwent endoscopy, and 16,743 in the control group. After a maximum follow-up of 12 years, non-cardia GC mortality was 13.1 per 100,000 person-years in the screening group and 13.5 per 100,000 person-years in the control group. Intention-to-treat analysis showed a 15% lower non-cardia GC mortality in the screening group compared with the control group (adjusted rate ratio [aRR], 0.85 [95% CI: 0.49-1.50]), although the difference was statistically non-significant. In the per-protocol analysis, the aRR for non-cardia GC mortality was 0.70 (95% CI: 0.38-1.29). A subgroup analysis of the screening group restricted to participants who complied with screening protocol and received timely treatment for detected malignancies yielded similar results, with an aRR of 0.66 (95% CI: 0.35-1.22); neither of these analyses reached statistical significance. In this trial, endoscopic screening was associated with a non-significant reduction in non-cardia GC mortality; larger trials in higher-incidence settings are needed to confirm a benefit.

First-line treatment of gastric cancer is evolving with the integration of immune checkpoint inhibitors (ICIs) and targeted agents, complicating biomarker stratification. Claudin 18.2 (CLDN18.2) is an established target for zolbetuximab; however, immunohistochemistry (IHC) is limited by tissue requirements, cost, and turnaround time. Artificial intelligence (AI) analysis of hematoxylin and eosin (H&E)-stained slides may provide a scalable alternative. We developed and validated an AI model to predict CLDN18.2 expression from H&E slides and evaluated its clinical utility integrated with AI-derived immune phenotyping. This retrospective study included three independent cohorts of patients with gastric cancer. The development cohort comprised 622 patients (497 for training and 125 for tuning). The internal validation cohort included 378 patients treated with first-line nivolumab plus chemotherapy or chemotherapy alone. The external validation cohort included 98 patients from diverse ethnic backgrounds. Whole-slide H&E-stained images were analyzed using a Vision Transformer-based AI model to predict CLDN18.2 expression. A separate AI model classified the immune microenvironment as inflamed or noninflamed. Primary outcomes were predictive performance metrics, including area under the receiver operating characteristic curve (AUROC). Secondary outcomes included progression-free survival (PFS) and overall survival (OS), stratified by AI-predicted CLDN18.2 status and immune phenotype. CLDN18.2 positivity by IHC was 42.9% (development), 36.8% (internal validation), and 25.5% (external validation). The AI model yielded AUROC values of 0.752 (internal validation) and 0.856 (external validation). In the internal validation cohort, patients with AI-predicted CLDN18.2-negative/inflamed tumors exhibited improved outcomes with nivolumab plus chemotherapy versus chemotherapy alone [PFS: hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.15-0.82; OS: HR 0.40, 95% CI 0.18-0.89]. Patients with CLDN18.2-positive/noninflamed tumors showed no benefit from nivolumab plus chemotherapy. An AI model using routine histology predicted CLDN18.2 expression and immune phenotype in gastric cancer, identifying subgroups with differential benefit from ICI-based chemotherapy.

A 68-year-old man with gastric cancer underwent 18F-fluorodeoxyglucose (FDG) PET/CT, which revealed an incidental subcutaneous lesion suspicious for low-grade sarcoma or metastasis. The patient initially declined a biopsy. One month later, following a new diagnosis of prostate cancer, 68Ga-prostate-specific membrane antigen (PSMA) PET/CT was performed. The unchanged lesion demonstrated heterogeneous, moderate PSMA uptake. Subsequent histopathologic examination confirmed the lesion as a spindle cell lipoma. In conclusion, spindle cell lipomas can exhibit mild 18F-FDG and moderate PSMA uptake, serving as a potential pitfall that can mimic malignancy and cause false-positive results in oncologic PET/CT imaging.

Gastric cancer (GC) remains a major cause of cancer‑related mortality worldwide, and only a subset of patients achieves durable benefit from immune checkpoint blockade (ICB). This suggests that non‑genomic barriers within the tumor microenvironment (TME) substantially limit antitumor immunity. Increasing evidence indicates that tumor‑intrinsic glycolytic reprogramming and lactate accumulation contribute to this immune resistance. Oncogenic signaling, hypoxia‑inducible factor‑1α (HIF‑1α), phosphoinositide 3‑kinase/protein kinase B/mechanistic target of rapamycin (mTOR) pathways and noncoding RNA networks promote the expression of glycolytic enzymes and lactate transporters, including hexokinase 2, 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 3 (PFKFB3), pyruvate kinase M2, lactate dehydrogenase A (LDHA) and monocarboxylate transporters, thereby establishing a glycolysis‑high, lactate‑rich TME. Within this metabolic niche, lactate functions as a bioactive mediator that impairs dendritic cell differentiation and cross‑priming, weakens cytotoxic T‑cell and natural killer‑cell activity, and promotes M2‑like macrophages and myeloid‑derived suppressor cells through hydroxycarboxylic acid receptor 1/G protein‑coupled receptor 81‑dependent signaling and histone lactylation. Cancer‑associated fibroblasts and mesenchymal stem/stromal cells further reinforce this state through glycolysis, lactate shuttling, cytokine secretion, extracellular matrix remodeling and exosome‑mediated transfer of glycolysis‑promoting noncoding RNAs. These interactions generate spatially organized immunometabolic niches characterized by lactate accumulation, stromal remodeling, abnormal angiogenesis and poor CD8+ T‑cell infiltration. The present review summarizes the molecular drivers of glycolytic reprogramming in GC, the mechanisms by which lactate‑centered crosstalk reshapes stromal and immune compartments, and emerging therapeutic strategies targeting LDHA/monocarboxylate transporter 4, PFKFB3, HIF‑1α/mTOR, epigenetic regulators and repurposed metabolic drugs in combination with programmed death‑1/programmed death‑ligand 1 blockade. It is also discussed how fluorine‑18 fluorodeoxyglucose positron emission tomography/computed tomography, radiomics, glycolysis‑ and lactylation‑related gene signatures, exosomal biomarkers and dynamic metabolic monitoring may support patient stratification and response prediction. Viewing selected GC subtypes through a glycolysis‑centered immunometabolic framework may help guide the rational integration of metabolic and immune interventions to overcome metabolically protected, ICB‑refractory disease.

The present study aimed to investigate the involvement of T‑box transcription factor 15 (TBX15) in the immune evasion by gastric cancer (GC) cells, as well as the molecular pathways that regulate TBX15 upstream and downstream. GC and paracancerous tissues were collected to verify the expression of TBX15, matrix metalloproteinase 14 (MMP14) and methyltransferase‑like 3 (METTL3) using reverse transcription‑quantitative PCR and western blotting. The co‑culture system of GC cell‑tumor‑associated macrophages (TAMs) and mouse forestomach carcinoma (MFC) cell‑CD8+ T cells was constructed. TBX15, MMP14 and METTL3 were highly expressed in GC tissues. Kaplan‑Meier analyses were performed, and high TBX15 expression predicted a poor prognosis for patients with GC. Silencing TBX15 promoted GC cell apoptosis and inhibited tumor development and the activity of proliferation, migration and invasion. TBX15 targeted the MMP14 promoter by using ChIP‑qPCR. Overexpression of MMP14 attenuated the reduction caused by TBX15 silencing. METTL3 targets TBX15 mRNA and regulates the m6A level of TBX15. TBX15 is associated with macrophage and CD8+ T cell infiltration. In the co‑culture system of GC‑TAM and MFC‑CD8+ T cells, TBX15 overexpression alleviated the decrease in M2 polarization and activation of CD8+ T cell antitumor activity caused by METTL3 silencing. However, MMP14 overexpression resulted in TBX15 silence‑induced decreases in M1 macrophage polarization and CD8+ T cell activity. These data suggested that TBX15, correlated with poor prognosis in patients with GC, promotes immune escape in GC cells. TBX15, regulated by m6A methylation, targeted the MMP14 promoter, thereby regulating MMP14 expression. The METTL3/TBX15/MMP14 signaling axis was involved in GC cell development, M2 macrophage polarization and CD8+ T cell antitumor activity activation. These findings provide a fundamental experimental rationale for TBX15 as a potential therapeutic target for GC.

Aurora kinase A (AURKA) is frequently overexpressed in gastrointestinal cancers. Helicobacter pylori (H. pylori) infection is a significant risk factor for gastric carcinogenesis. LGR5, a stem cell marker in the stomach, plays an important role in gastric tumorigenesis. This study investigates the link between AURKA and LGR5 in response to H. pylori infection in gastric cancer. We analyzed publicly available datasets, gastric cancer cell lines, patient-derived organoids and xenografts (PDOs and PDXs), mouse models, and de-identified human tissue samples. We found a strong association between AURKA and LGR5 expression levels in gastric cancer tissues. In vitro and in vivo analyses showed increased AURKA and LGR5 protein levels in response to H. pylori infection. Using cell models and PDOs, we demontrated an AURKA-dependent induction of LGR5, whereas genetic knockdown or pharmacologic inhibition of AURKA abolished the H. pylori-induced increase in LGR5 by enhancing LGR5 ubiquitination. Mechanistically, AURKA interacted with STAMBP, suppressing LGR5 deubiquitination and thereby promoting its stabilization. Using a tamoxifen-induced conditional knockout (CKO) mouse model of Aurka (Krt19CreErt/Aurkaflox/flox), we detected a lower baseline expression of LGR5 in gastric glands, with reduced induction following H. pylori infection, compared to controls. The Aurka CKO mouse model was crossed with the Tff1-/- model of gastric tumorigenesis to create the Krt19CreErt/Aurkaflox/flox /Tff1-/- mouse model. AURKA knockout, after tamoxifen treatment, significantly reduced the LGR5 protein level and led to a marked decrease in antral thickness. In PDX models, the use of a combination treatment of AMG900 (a pan-AURORA inhibitor) with docetaxel was more effective than monotherapy, lowering LGR5 levels and suppressing tumor growth. In summary, there is a functional link between AURKA and LGR5, mediated by STAMBP to promote stem-like properties and enhance cell survival in gastric tumorigenesis. Targeting the AURKA-LGR5 axis is a potential therapeutic strategy.

This study aimed to investigate how the CXCL12/CXCR4 axis facilitates immune evasion in gastric cancer (GC) by enhancing cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) using single-cell transcriptome sequencing. Single-cell RNA sequencing of tumor and normal gastric tissues in a murine GC model revealed an increased macrophage population in GC, characterized by predominantly M2-polarized TAMs. The study identified that the CXCL12/CXCR4 axis potentially triggers M2 macrophage polarization through mediating communication between CAFs and TAMs. In vitro experiments confirmed that CAFs induced M2 polarization through CXCL12/CXCR4 signaling. Inhibition of the PD-L1/PD-1 axis disrupted communication between M2 macrophages and T cells, which enhanced T cell activation. In vivo experiments showed that silencing CXCR4 reduced M2 macrophages and PD-L1 expression, leading to improved T cell proliferation, reduced immune evasion, and slower tumor growth. These findings highlight the role of the CXCL12/CXCR4 axis in driving immune evasion in GC by inducing M2 polarization and PD-L1-mediated T cell suppression, and indicate a promising therapeutic target for GC immunotherapy. Schematic Molecular Mechanism Illustrating CXCL12/CXCR4 Axis-Mediated Cellular Communication between CAFs and TAMs Promoting Gastric Cancer Immune Evasion.

Metastasis in gastric cancer requires metabolic reprogramming, but its key drivers remain unclear. Using a CRISPR-Cas9 metabolic knockout screen integrated with patient transcriptomes, we identified the mitochondrial enzyme ALDH6A1 as an anti-invasive factor. ALDH6A1 down-regulation blocked the terminal step of valine catabolism and caused intracellular accumulation of methylmalonic acid (MMA). MMA competitively occupied the α-ketoglutarate (α-KG) cofactor pocket of the histone demethylase KDM5C, suppressing its activity and increasing H3K4 dimethylation (H3K4me2) at promoters of invasion-related genes, including ANGPT2 (angiopoietin-2) and MMP7 (matrix metalloproteinase 7). This epigenetic reprogramming promoted gastric cancer liver metastasis in mice. Pharmacologic ALDH6A1 activation with Alda-1 or systemic MMA clearance with l-carnitine lowered H3K4me2, dampened the invasive program, and reduced metastatic burden. These findings identify the ALDH6A1-MMA axis as a targetable metabolic-epigenetic pathway in gastric cancer metastasis.

Peritoneal metastasis is the leading risk factor for gastric cancer (GC). However, the mechanism of gastric cancer peritoneal metastasis (GCPM) is still unclear. GCPM depends not only on the "seeds" of tumor cells but also on the "soil" of the peritoneal microenvironment. This study aimed to analyze the changes in the peritoneal tissue microenvironment of nine patients with early-stage GC, advanced-stage GC, and GCPM using single-cell transcriptome sequencing. It found that the number of microfiber-associated protein 2 (MFAP2)-positive cancer-associated fibroblasts (CAFs) gradually increased with tumor progression and was associated with poor prognosis of GC during GCPM progression. Mechanistically, GC cells secreted transforming growth factor-β1 (TGF-β1) to stimulate the entry of Smad4 into the nucleus. This promoted the transcription of MFAP2 in peritoneal mesothelial cells and led to mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells into CAFs, thereby altering the peritoneal microenvironment and facilitating the colonization of GC cells on the peritoneum. Moreover, MFAP2 secreted by CAFs bound to the integrin αVβ3 receptor on the surface of GC cells, activating the Src-STAT3 signaling pathway and upregulating the expression of protein tyrosine kinase 7 (PTK7) in GC cells. PTK7 accumulated intracellular β-catenin and facilitated its nuclear entry, activating transcription of downstream target genes to enhance the invasion and adhesion of GC cells, thereby promoting GCPM progression. Our findings provide insights into how changes in the peritoneal microenvironment promote the peritoneal metastasis of GC, thus providing new molecular targets for personalized treatment and prognostic evaluation in clinical practice.

The stomach regenerates its glands after environmental insults by reconstructing diverse cell types. In this issue of Developmental Cell, Loe et al.1 show that ARID1A safeguards regeneration and recovery by maintaining cell lineage identity, whereas compromised lineage integrity following Arid1a loss, together with Trp53, can promote aggressive gastric cancer.

Peritoneal dissemination is a major cause of mortality in gastric cancer (GC), yet its molecular underpinnings remain incompletely defined. By integrating single-cell transcriptomic profiling of primary tumors and peritoneal lesions with functional and mechanistic studies, we identified a hypoxia-sensitive GC cell population that emerges during peritoneal metastasis and exhibits heightened autophagic activity and metastatic potential. Hypoxic stress robustly induced the deubiquitinase USP33 in GC cells, and high USP33 expression correlated with adverse clinical outcome. Gain- and loss-of-function assays demonstrated that USP33 enhances autophagy and promotes proliferation, invasion, and survival of GC cells. Proteomic and biochemical analyses revealed that USP33 directly interacts with the autophagy regulator ATG101 and stabilizes it by removing K48-linked polyubiquitin chains at lysine residues 106 and 191, thereby sustaining autophagic flux and facilitating peritoneal colonization. Upstream, hypoxia activated EPAS1/HIF2A, which bound to and transcriptionally upregulated USP33, establishing a hypoxia-responsive EPAS1-USP33-ATG101 axis. Disruption of this axis, either by USP33 silencing or pharmacological inhibition of EPAS1, suppressed autophagy-dependent peritoneal metastasis and prolonged survival in vivo. Collectively, our findings define a mechanistic link between hypoxia, oncogenic autophagy, and peritoneal dissemination in GC, and highlight the EPAS1-USP33-ATG101 axis as a promising therapeutic target in advanced disease.

Exposed constantly to environmental challenges, the stomach undergoes highly reversible cycles of regeneration and recovery. Although abnormal activation of regeneration is known to be associated with cancer, the mechanisms underlying tissue restoration remain unclear. Our single-cell gene expression and chromatin analysis defined cell state dynamics during regeneration and recovery, identifying the Brahma-related gene 1(BRG1)/BRM-associated factor (BAF) chromatin remodeling complex during recovery. Strikingly, deletion of AT-rich interaction domain 1A (Arid1a), a subunit of the BAF complex and the second most frequently mutated gene in gastric cancer, impaired recovery across multiple murine injury models, resulting in a persistent regenerative state. Integrative analyses combining single-cell multiome and chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that the BAF complex recruits lineage-specific transcription factors such as MIST1 and estrogen related receptor gamma (ERRγ) to regulate enhancers of recovery genes. Notably, deletion of Trp53 in the unresolved regenerative state caused by Arid1a loss is sufficient to drive cancer development and invasion, revealing the epigenetic mechanisms bridging gastric regeneration, recovery, and cancer.

CDH1 is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline CDH1 mutations underlie most cases of the cancer syndrome hereditary DGC. We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of Cdh1 in the mouse stomach. We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the Cd44 promoter with a tdTomato reporter. Two models were developed, one with Cdh1-knockout alone (Cd44-Cre/tdTomloxP/loxP/Cdh1loxP/loxP (Cdh1-KO)) and a second more aggressive model with combined Cdh1 and Trp53 knockout (Cd44-Cre/tdTomloxP/loxP/Cdh1loxP/loxP/Trp53loxP/loxP (Cdh1-KO/Trp53-KO)). Cdh1 inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1 week of induction and intramucosal DGC (stage pT1a) within 2 months. By 9 months, 50% of mice had developed advanced (pT3) DGC. The morphology of most gastric carcinomas was comparable to human DGC, exhibiting poorly cohesive SRC and poorly differentiated cells. Additional Trp53 knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, Cdh1-KO/Trp53-KO mice frequently developed thymic lymphomas and soft tissue sarcomas. DNA sequencing did not find evidence of additional genetic events necessary for cancer progression in either model. Organoids derived from Cdh1-KO and Cdh1-KO/Trp53-KO mice showed a disrupted morphology with SRCs displaced out of the epithelial plane. Transcriptional changes associated with processes including cell-to-cell adhesion, interaction with the actin cytoskeleton and NF-κB signalling were observed. Inactivation of Cdh1 alone in Cd44-expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent Trp53 inactivation.

The long-chain acyl-CoA synthetase (ACSL) family has been associated with tumor progression across various cancer types. However, the function of the ACSL family in gastric cancer (GC) remains poorly understood. Comprehensive investigations employing in vivo and in vitro experiments demonstrate that ACSL3 suppresses ferroptosis and drives GC progression. Mechanistically, ACSL3 facilitated YY1 nuclear translocation, triggering endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR). Genome-wide binding analysis revealed that YY1 directly binds to the USP37 promoter, enhancing its transcriptional activation. Furthermore, a novel interaction was identified between USP37 and PERK, a pivotal UPR regulator, wherein USP37 mediates K29-linked deubiquitination of PERK. PERK stabilization upregulated SLC7A11 expression, thereby inhibiting ferroptosis and promoting tumor progression. Collectively, the findings establish a molecular cascade wherein ACSL3 mediates ER stress-mediated UPR activation through the YY1/USP37/PERK axis, suppressing ferroptosis and accelerating GC progression, identifying ACSL3 as a potential therapeutic target for GC treatment.

Gastric cancer remains a major cause of cancer mortality, and long-term control is still limited by recurrence, metastasis, and therapy resistance, creating a clear need for small molecules that act through noncanonical mechanisms. Lysosomes have become an attractive target because loss of lysosomal competence can translate into cytoplasmic vacuolization, impaired autophagic turnover, and ultimately cell death. Nur77 is a stress-responsive nuclear receptor implicated in tumor biology, but whether it can be pharmacologically harnessed to drive lysosome-centered vulnerability in gastric cancer has not been well established. Here, we designed and synthesized a series of 2-(6-(4-methoxyphenyl)-2-methylnicotinoyl)-N-substituted carboxamide/carbothioamide derivatives and identified compound 6K as the lead. 6K potently inhibited the growth of gastric cancer cells while showing low cytotoxicity toward normal gastric epithelial cells. In both HGC-27 and AGS cells, 6K reduced viability and clonogenic survival and rapidly induced prominent cytoplasmic vacuolization. In HGC-27 cells, 6K further caused LC3-II and p62 accumulation, loss of Lyso-Tracker signal, and partial rescue of vacuolization and colony formation by bafilomycin A1. 6K also induced apoptosis, supported by increased PARP cleavage, TUNEL positivity, and Annexin V/PI staining. Mechanistically, 6K directly bound the Nur77 ligand-binding domain, and Nur77 overexpression attenuated 6K-driven lysosomal perturbation and apoptotic signaling. In an HGC-27 xenograft model, 6K at 20 mg/kg significantly suppressed tumor growth without obvious histopathological injury to major organs. Collectively, these findings define 6K as a tractable Nur77 modulator that couples lysosomal dysfunction to apoptotic death in gastric cancer, providing a lead scaffold for lysosome-directed anticancer therapy.

Anticoagulation is frequently prescribed for prophylaxis of venous thromboembolic events (VTE) such as deep vein thrombosis (DVT) or pulmonary embolism (PE) following bariatric surgery. Currently, there are no established guidelines on peri-procedural management of VTE after endoscopic sleeve gastroplasty (ESG), a less invasive treatment option for obesity. This study aims to determine the incidence of DVT and PE within 30 days after ESG and evaluate current practice patterns of peri-procedural VTE prophylaxis. Patients who underwent ESG from 2020 to 2023 from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database were analyzed. Pre-operative incidence of DVT, therapeutic anticoagulation, venous stasis, and VTE prophylaxis methods were collected. The primary outcome was the frequency of post-ESG DVT and PE at 30 days. Secondary outcomes were methods of VTE prophylaxis and co-morbid predictors of VTE from ESG. A total of 2371 ESG patients (mean age 45y, 85.8% F, mean BMI 40) were included in this study. Prior to ESG, 29 (1.2%) had a history of DVT and 38 (1.6%) were on therapeutic anticoagulation. For VTE prophylaxis, 1106 (46.7%), 16 (0.7%), 295 (12.4%), and 954 (40.2%) were mechanical, pharmacologic, mechanical and pharmacologic, or none. The 30-day incidence of postoperative DVT and PE was 7 (0.3%) and 5 (0.2%). Two-thirds of patients who developed VTE were not on prophylaxis prior to ESG. The incidence of VTE following ESG is extremely low in this large prospective multicenter database. Although events occurred in fewer than 0.5% of cases, a majority of patients who developed DVT or PE after ESG did not receive pharmacologic or mechanical prophylaxis. Decisions surrounding the selection of VTE prophylaxis should be made based on a patient's co-morbidities, with consideration for low-risk interventions like mechanical prophylaxis in all patients undergoing ESG.

Weight loss and weight loss maintenance are prominent topics of discussion for clinicians and health professionals involved in treatment to reduce obesity and the risk of cardiovascular disease. Because physical activity is a key component of comprehensive obesity treatment, this scientific statement summarizes the role of physical activity in promoting weight loss, weight loss maintenance, and cardiometabolic health, complementing lifestyle, pharmacological, and surgical-based weight loss intervention strategies. Independently of weight loss, physical activity and exercise programs improve major cardiometabolic risk factors, including hypertension, insulin resistance, and dyslipidemia, which are highly prevalent in patients with overweight or obesity. As a single treatment modality, physical activity and exercise programs are unlikely to result in clinically meaningful weight loss (ie, at least 5% loss of initial body weight) unless aerobic physical activity levels are exceptionally high. When combined with diet-induced negative energy balance, obesity medication, or surgical treatment, increased physical activity can augment total weight loss and improve cardiometabolic outcomes. Because clinicians and health professionals play a pivotal role in fostering and sustaining patients' health goals, this scientific statement also provides an overview of evidence-based strategies for targeted weight loss counseling and for leveraging digital technology, particularly to engage patients and achieve realistic physical activity goals.

Post-treatment surveillance after locally treated colorectal liver metastases involves CEA measurement and contrast-enhanced CT (CECT) scans. However, reactive tissue around ablated lesions can appear similar to viable tumor tissue on CECT, complicating the detection of local tumor progression (LTP). Therefore, a new imaging protocol was initiated, which incorporates [18F]FDG-PET/CT to complement CECT. This study evaluated the diagnostic accuracy of [18F]FDG-PET/CECT for early detection of disease progression after resection or thermal ablation, compared to CECT alone. The study analyzed a prospective cohort of patients undergoing thermal ablation or resection, who received CECT and [18F]FDG-PET/CT scans 3-5 months post-treatment. Disease progression was confirmed by histology, consensus during a multidisciplinary team meeting or after extended follow-up. Diagnostic accuracy of [18F]FDG-PET/CECT was compared to standard practice (CEA serum levels and CECT). The final analysis included 64 patients with 154 lesions. 37 patients underwent ablation, 14 patients underwent resection, and 13 patients underwent combination therapy, resulting in 93 (60%) lesions being treated with thermal ablation and 61 (40%) lesions with resection. Disease progression was found in 66% of patients, with LTP detected in 25% of treated lesions. Compared to CECT, [18F]FDG-PET/CECT had a higher diagnostic accuracy for detecting local progression after thermal ablation (AUC 0.97 vs. 0.73, p = 0.001) and hepatic resection (AUC 0.96 vs. 0.69, p = 0.03), and for detection of extrahepatic disease (AUC 0.91 vs. 0.79, p = 0.03). CEA serum levels had low diagnostic accuracy for detecting disease progression (AUC 0.60). [18F]FDG-PET/CECT improves diagnostic accuracy in the early follow-up of patients with locally treated colorectal liver metastases. Question: Interpreting CECT scans after local treatment of colorectal liver metastases can be challenging because reactive tissue around treated lesions can appear similar to viable tumor tissue. [18F]FDG-PET/CECT improves the diagnostic accuracy of detecting local tumor progression after thermal ablation and resection of colorectal liver metastases. [18F]FDG-PET/CECT should be considered during follow-up after local treatment of colorectal liver metastases to identify and treat local tumor progression earlier.

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, and liver metastases stands as a leading contributor to its high mortality rate in advanced stages. Regorafenib plus anti-PD-1 is a new therapeutic option for patients with colorectal cancer liver metastases (CRCLM). However, a considerable number of patients have not benefited from it. In this study, KRAS mutation was identified associated with resistance to regorafenib plus anti-PD-1 in CRCLM. Dihydroartemisinin (DHA), a clinically approved anti-malaria agent, was verified to selectively downregulate KRASG12D mutant with no discernible influences on wild-type KRAS, which is consistent with the higher sensitivity of KRAS-mutant CRC cells and organoids to DHA treatment. In preclinical KRASG12D CRCLM models, DHA substantially potentiated the therapeutic efficacy of regorafenib plus anti-PD-1 by remodeling the tumor immune microenvironment, including enhancing the cytotoxicity of CD8+ effector T cells and promoting pro-inflammatory macrophage polarization. Mechanically, DHA could restore interferon response that was impaired by oncogenic KRAS mutations, and inhibit ERBB signaling activation induced by regorafenib. Collectively, these findings support DHA as a potential adjunct to regorafenib plus anti-PD-1 for KRASG12D CRCLM and suggest a therapeutic strategy with translational potential for KRAS-driven malignancies.Black arrows: Mutant KRAS can impair IFN response to inhibit CD8+ T cells anti-tumor immune response, thus attenuating the efficacy of PD-1 mAb therapy. Red arrows: DHA can inhibit mutant KRAS expression by promoting autophagy-lysosome pathway. Orange arrows: Regorafenib plays a role of anti-angiogenesis, but also probably induces ERBB signaling activation, which can inhibit IFN response via upregulating p-Erk1/2 and p-Akt, thus causing resistance to regorafenib treatment. Green arrows: The treatment of DHA can drive macrophages polarization to pro-inflammation phenotype (M1-like), probably via the enhancement of TNFα expression. This Figure was produced by Figdraw.

Endoscopic closure techniques are essential for management of endoscopic defects and help prevent delayed bleeding and perforation. The SutuArt endoscopic hand-suturing system (EHS) is an innovative method for defect closure, but clinical data remain limited. In a multicenter European registry study, all procedures using EHS from 14 centers were evaluated. The primary endpoint was technical success, defined as complete defect closure without additional closure techniques. Secondary endpoints were in-hospital clinical success (absence of post-interventional complications); overall defect closure rate (closure achieved with additional devices) and procedure time. Between February 2023 and January 2026, 338 procedures were included. Indications comprised 240 ESD (Endoscopic Submucosal Dissection), 32 EID (Endoscopic Intermuscular Dissection), 41 G-POEM (Gastric Peroral Endoscopic Myotomy), 10 fistulas, 6 EMR (Endoscopic Mucosa Resection), 3 STERs (Submucosal Tunneling Endoscopic Resection), 2 NEWS (Non-exposed Endoscopic Wall inversion Surgery), 1 anastomotic leak, 1 perforation, 1 EFTR (Endoscopic Full Thickness Resection) and 1 endoscopic hemostasis. The median defect size was 35 mm (range 4-155 mm), the median suturing time was 25 minutes (range: 4-120). Technical success was 96.2% (325/338). Overall defect closure rate was 96.7% (327/338). In-hospital clinical success was 97.9% (331/338). Defect size did not predict suturing time in the global size-time model, indicating that procedural complexity was not explained by size alone. Procedure-related adverse events occurred in 5/338 (1.5%), overall AEs were 10/338 (3%). EHS demonstrated high technical and in-hospital clinical success with a low observed short-term adverse event rate. Further studies are needed to assess the performance for complex defects.

To compare efficacy and safety of topical trichloroacetic acid (TCA) versus electrocautery (ECA) for the treatment of human papillomavirus (HPV)-associated anal intraepithelial neoplasia (AIN) in people living with HIV (PLWH). The TECAIN-study was a prospective, multicentre, randomised (1:1 block-randomisation), open-label, non-inferiority trial in PLWH with histologically confirmed AIN recruited from seven German proctological units. The primary endpoint (PE) was therapeutic success defined as a combination of complete clinical response evaluated by high-resolution-anoscopy and histological AIN-clearance/regression four weeks after the end-of-treatment (4-weeks-follow-up, 4WFU). Secondary endpoints were assessed at 4WFU and 24WFU. Efficacy was analysed in the intention-to-treat-population as primary analysis with a non-inferiority margin of -12%. Of 659 PLWH screened with HRA, 257 patients with AIN were randomised. Therapeutic outcome was assessed in 233 PLWH (TCA n = 118, ECA n = 115). The PE was reached in 62 patients of the TCA-group (52.5%) versus 71 patients of the ECA-group (61.7%) (difference in proportion - 9.2%, 95%CI -21.8% to 3.5%). While non-inferiority of TCA could not be shown for the PE at 4WFU, TCA was non-inferior to ECA at 24WFU (therapeutic success 50.8% vs. 48.7% (difference 2.2%, 95%CI -10.7% to 15.0%)). Adverse events occurred in 67.8% in both groups at 4WFU (mostly mild or moderate). Severe treatment-related pain was significantly less frequent in the TCA-group (4.2%) compared to the ECA-group (14.8%). HPV-findings did not differ between treatment groups between baseline and follow-up visits. TCA is an effective, well-tolerated and less complex alternative to ECA for the treatment of AIN in PLWH.

Appendiceal goblet cell adenocarcinomas (GCAs) are rare and preferentially spread to the peritoneum. They comprise differing histological patterns with variable prognosis. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS + HIPEC) is offered in specialist centres for eradication of peritoneal metastases, but the role of systemic chemotherapy is unclear. This study aimed to evaluate the long-term outcomes and prognostic factors of GCA patients using the World Health Organisation (WHO) 2019 grading following CRS + HIPEC and the role of systemic chemotherapy. Patient data from a peritoneal tumour centre were identified through a prospective database and histopathology archive (1993-2021). Patients were selected for CRS + HIPEC based on disease distribution and burden. Cases were re-reviewed for histological and two-tiered grading. Systemic chemotherapy was categorised into curative (neo/adjuvant) and palliative intent. The primary endpoint was overall survival (OS). There were 210 patients with GCA who had 60% localised disease (M0) and 40% peritoneal metastases (M1) at diagnosis. CRS was carried out on 135 (64%) patients and systemic chemotherapy was given to 85 (40%) patients: 11 (13%) neoadjuvant, 9 (11%) adjuvant and 52 (61%) palliative. After multivariable analysis, positive lymph nodes, peritoneal metastasis, no perforation, no CRS and systemic chemotherapy were associated with increased risk of death (P < 0.05). Re-categorisation of the cohort into two-tiered grading showed improved stratification compared with Tang or WHO 2019 grading. Systemic chemotherapy was associated with benefit for patients with high-grade disease, positive lymph nodes and completeness of cytoreduction score CC1-3 CRS (P < 0.05). This study represents the largest non-registry cohort of appendiceal GCA that evaluates prognostic factors. It outlines outcomes after CRS + HIPEC and provides a comprehensive analysis of the WHO 2019 grading with consideration of a two-tiered system for better risk stratification and selection of patients for systemic chemotherapy.

Autoantibodies neutralising interleukin-10 (IL-10) have recently been described as a mechanism of inflammatory bowel disease (IBD); however, prevalence and clinical impacts are unknown. To determine the prevalence and longitudinal persistence of IL-10 autoantibodies in a population of paediatric-onset IBD and to assess associated clinical features. We analysed plasma IL-10 autoantibodies with a cross-sectional study of a paediatric cohort of patients diagnosed with either IBD (n=239), autoimmune enteropathy (n=37) or congenital diarrhoea and enteropathies (n=42). Functional testing to assess IL-10 response was performed using cell-based assays under biologically relevant stimulation. Five patients with autoantibodies neutralising 2.5 ng/mL of IL-10 were identified, three of whom were also neutralising at 5 ng/mL. All had IBD without a known monogenic cause. Longitudinal samples (available in three of five subjects) showed autoantibody persistence in two cases, 3 and 9 years after baseline. The patient without persistence had undergone haematopoietic stem-cell transplantation (HSCT) 2 years after baseline sampling. The prevalence of neutralising IL-10 autoantibodies was 2.1% (95% CI 0.7% to 4.8%), while the frequency was 2.6% in subjects without IBD-associated monogenic variants (n=192). In paediatric autoimmune and inflammatory gut diseases, IL-10 neutralising autoantibodies were detected only among patients with IBD without known genetic aetiology. Patients had heterogeneous clinical characteristics and IL-10 autoantibodies persisted under standard immunosuppressive treatment but disappeared following HSCT and may have declined with colectomy or ileostomy. Screening for IL-10 autoantibodies via functional assays may identify a subgroup of patients with distinct aetiology and therapeutic needs.

Patients with advanced biliary tract cancers (aBTC) are in urgent need of additional/new treatment options. We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy in patients with aBTC. In this multicenter, open-label, phase II study, 30 patients with treatment-naive unresectable locally advanced or metastatic BTC received ivonescimab (20 mg/kg or 30 mg/kg) combined with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) every 3 weeks for up to eight cycles, followed by ivonescimab maintenance. The primary endpoint was the investigator-assessed objective response rate (ORR) and safety. Pretreatment tumor specimens available from the trial were subjected to a post hoc exploratory proteomic analysis. The correlation between MAP2K7 levels and ivonescimab efficacy was assessed by BTC tumor cell-T cell co-culture and BTC organoids-T cell. At data cutoff, 1 patient achieved complete response and 19 patients achieved partial response yielding an ORR of 66.7% (95% Confidence Interval [CI]: 47.2-82.7). The disease control rate was 100%. The median progression-free survival (mPFS) was 8.5 months (95% CI: 7.6-10.5) and the median overall survival (mOS) was 16.8 months (95% CI: 11.1-22.5). Treatment-related adverse events occurred in 100.0% of patients with the most common being anemia (25, 83.3%), neutrophil count decreased (23, 76.7%), white blood cell count decreased (22, 73.3%), and platelet count decreased (22, 73.3%). No treatment-related deaths occurred. Additionally, exploratory proteomic and functional analyses identified MAP2K7 as a resistance-associated biomarker. MAP2K7 was upregulated in non-responders, and MAP2K7 suppression enhanced ivonescimab-mediated antitumor activity in immune co-culture models. Ivonescimab plus chemotherapy showed potential anti-tumor activity and tolerable safety as first-line treatment of aBTC patients. Exploratory analyses suggest that MAP2K7 may serve as a candidate biomarker of resistance and a potential therapeutic target for optimizing ivonescimab-based therapy of aBTC patients. Currently, the standard of care for first-line therapy in patients with aBTC is the addition of immune checkpoint inhibitors to chemotherapy based on the TOPAZ-1 and KEYNOTE-966 trials. However, this new regimen only improved OS by less than 2 months. The ORR of 66.7%, DCR of 100% and the median overall survival of 16.8 months were observed with ivonescimab plus chemotherapy. This study provides evidence supporting the potential role of ivonescimab plus chemotherapy as a first-line therapy for patients with treatment-naive unresectable locally advanced or metastatic BTC. NCT05214482 and NCT06048289. NCT05214482 and NCT06048289.

The use of peptide receptor radionuclide therapy (PRRT) is well established in the treatment of advanced or unresectable neuroendocrine tumours (NETs) after progression on somatostatin analogues (SSA), with randomised clinical trials such as NETTER-1 and NETTER-2 showing improvement in progression free survival (PFS) as well as tumour response [12, 13]. Current landmark trials only considered patients suitable for PRRT if all known lesions displayed SSTR expression, via avidity on planar scintigraphy or Gallium-68 DOTATATE PET/CT. However, there is a select group of patients with oligodiscordant disease (3 or less lesions which are FDG avid but not DOTATATE avid) on dual DOTATATE/FDG PET imaging who may benefit from PRRT in combination with additional therapies such as liver directed therapy (LDT) or chemotherapy. There is currently no data regarding the efficacy and outcomes of PRRT in oligodiscordant disease. This study is the first to describe the treatment patterns and outcomes of patients with oligodiscordant disease receiving PRRT. A single-centre retrospective review was performed in patients with advanced gastroenteropancreatic NETs with oligodiscordant disease who received at least one cycle of PRRT with [177Lu]Lu-DOTA-TATE from 2020 to 2024. Safety was assessed by renal and haematological parameters (CTCAE v5.0) during PRRT, and at 3 months post completion of treatment. Response to treatment was evaluated on molecular imaging with Gallium-68 DOTATATE PET/CT. Kaplan-Meier method was used to perform median progression free survival (PFS), overall survival (OS), and time to next treatment (TTNT) analyses. Thirteen patients met the inclusion criteria, the median age was 66 years, and 54% were male. Primary site: small bowel (7), pancreas (4), colorectal (2). WHO grade: none had grade 1 disease, ten grade 2 and three had grade 3 disease. Median OS was 27.3 months (95% CI 19.7 - not reached), median PFS 15.1 months (95% CI 7.1-20.1), and median TTNT 15.0 months (95% CI 6.7-39.6). One of 15 patients developed treatment related myeloid neoplasm on long term follow-up, confirmed by bone marrow biopsy. No patients developed significant renal toxicity on follow-up. In patients with advanced NETs with oligodiscordant disease identified on dual PET imaging, the combination of PRRT with systemic therapy or other therapies (surgery, liver directed therapy, radiotherapy) can be effective with acceptable toxicity and should be considered as a possible option for treatment in selected patients. The sequencing of treatment modalities and exact strategy employed is best decided at an experienced NET centre with multi-disciplinary input.

The prevalence of type 2 diabetes mellitus (T2DM) is rising rapidly in China and is linked to increased cancer risk, but causality remains unclear due to biases. We examined the causal effect of T2DM on cancer risk using bias-minimizing methods. We conducted a matched cohort study within China Kadoorie Biobank (median follow-up 49 months in men and 53 months in women). To minimize bias, we included only new-onset T2DM, applied sequential longitudinal matching, used pre-diagnosis BMI, and accounted for detection time bias. Stratified Cox models estimated sex-specific time-split hazard ratios (tsHRs). Results were triangulated with two-sample Mendelian Randomization (MR) in East Asians. After 1:3 matching, 8657 men and 13,680 women with T2DM were matched to unexposed individuals. T2DM was associated with increased risk of total cancers in men (tsHR 1.57, 95% CI 1.38-1.78) and women (tsHR 1.29, 95% CI 1.14-1.46). Site-specifically, T2DM was associated with liver cancer (men: 68 cases, tsHR 2.12, 95% CI 1.42-3.15; women: 43 cases, tsHR 2.39, 95% CI 1.42-4.04) and pancreatic cancer (men: 36 cases, tsHR 2.57, 95% CI 1.35-4.92; women: 33 cases, tsHR 3.95, 95% CI 1.92-8.13). No significant associations were observed for colorectal, lung, stomach, or breast cancers. In multivariable MR, genetic liability to T2DM was associated with pancreatic cancer after adjusting for BMI (OR 1.07, 95% CI 1.01-1.14, p = 0.03). In this large Chinese population, we found evidence for causal associations between T2DM and pancreatic cancer only, whereas evidence for other cancers was weak or discordant.

Reports on socioeconomic inequalities in cancer mortality are limited in East Asia. We investigated educational inequalities in cancer mortality in Japan, serving as an advanced example of a nationwide census-based surveillance. We developed a Japanese census-linked mortality dataset, using our unique linkage method. The dataset encompassed approximately 0.48 million cancer deaths linked to individual-level census data of 80 million Japanese aged 25-84 years in October 2020. We calculated age-standardised all-cancer and 23 site-specific cancer mortality rates (ASMRs) by educational level. Educational inequalities were quantified using the Relative Index of Inequality (RII) and Slope Index of Inequality (SII) by educational level (high, middle and low). Site-specific cancer contribution to absolute educational inequalities in all cancers was evaluated using the proportions of SII (%: SIICancer-site/SIIAll-cancer×100). All cancers' RIIs were 1.58 (95% CI 1.56 to 1.60) and 1.43 (1.40 to 1.46) in men and women, respectively. Among men, the rectum, stomach, liver and lung were the leading sites based on site-specific cancer RIIs, while the larynx, cervix uteri, liver and lung were the leading sites among women. In absolute terms, lung cancer contributed the most to educational inequalities, followed by stomach, colorectal and liver cancers. No educational inequality was found for pancreatic cancer. Breast cancer showed higher ASMRs among women with low education levels than among those with high education levels, which differed from the previous inequality pattern. Equity-focused strategies to enhance primary and secondary prevention are essential and should be supported by comprehensive nationwide monitoring.

Multiple primary carcinomas (MPC) represent a clinically significant yet underexplored phenomenon, where patients develop more than one distinct primary malignancy. While prior studies have examined MPC within specific cancer types, comprehensive real-world patterns of primary malignancies and their subsequent primary malignancies remain limited. Moreover, the survival outcomes associated with these MPC patterns, particularly in relation to demographic and clinical characteristics, are not well characterized. This study aimed to establish the patterns and combinations of MPC across a wide range of cancers and to assess whether the mortality status of patients with MPCs varies according to their demographic characteristics and disease status. We conducted a retrospective analysis of 1560 patients with MPC in Shanghai, China, from 2002 to 2015. Data were extracted from the Shanghai Cancer Registry, with follow-up until December 2017. Cause of death was ascertained through linkage with the Shanghai Vital Registration System. The distribution of the frequency and proportion of primary carcinoma (PC) combinations were depicted, and a life table was used to calculate the 1- to 5-year survival rates. Cox regression analysis was performed to analyze the survival risk factors of the first and second PCs. Among the 1560 patients (809/1560, 51.86% male and 751/1560, 48.14% female), the most frequent first PCs were colorectal, breast, and stomach cancers, while the most frequent second PCs were lung, colorectal, and stomach cancers. The most common combinations included colorectal and lung, colorectal and stomach, and colorectal and prostate. Survival rates were lowest for first PCs of skin (5 years=46.95%) and lung (5 years=41.54%) cancers, and for second PCs of pancreatic (5 year=9.13%) and liver (5 years=14.19%) cancers. A latency period of 12 months between PC diagnoses was associated with significantly higher cancer-specific mortality for both the first primary cancer (hazard ratio [HR] 3.539, 95% CI 2.822-4.438; P<.001) and the second primary cancer (HR 1.369, 95% CI 1.103-1.699; P=.004). Older age (>65 years) and advanced tumor stage (III+IV) were also significant independent risk factors for poor survival in both first PC (age: HR 2.049, 95% CI 1.689-2.485; P<.001; stage: HR 1.496, 95% CI 1.315-1.703; P<.001) and second PC (age: HR 1.575, 95% CI 1.242-1.996; P<.001; stage: HR 3.933, 95% CI 3.182-4.861; P<.001) analyses. This study provides a comprehensive, real-world map of MPC patterns and highlights important findings: high-risk cancer combinations and key factors associated with poorer survival, including a short interdiagnosis interval (12 months), advanced age, and advanced tumor stage. Comprehensive prevention and control strategies for MPC should be developed, and clinicians should be aware of the risks of MPC in vulnerable populations during the early diagnosis stage.

Helicobacter pylori colonizes the gastric mucosa of around half of the world's population and is a major cause of chronic gastritis, peptic ulcer disease, and gastric cancer. Current therapies are becoming increasingly ineffective due to the rapid spread of antibiotic resistance, creating an urgent need for new treatment options with distinct mechanisms of action. Drug repurposing offers a practical and cost-effective approach to address this gap. PBT2 is an 8-hydroxyquinoline derivative originally developed for the treatment of neurodegenerative diseases and has more recently been shown to possess antimicrobial activity. In this study, we demonstrate that PBT2 displays potent bactericidal activity against H. pylori, including multidrug-resistant clinical isolates. PBT2 rapidly killed H. pylori in vitro at low concentrations, with faster killing kinetics than commonly used antibiotics, and no resistance was detected after 30 days of continuous exposure. Importantly, PBT2 was effective in clearing an H. pylori infection in a murine model. Quantitative sequential window acquisition of all theoretical-mass spectrometry proteomic analysis revealed that PBT2 triggers broad disruption of essential bacterial processes, including global suppression of translation, impairment of iron-sulfur cluster assembly and respiration, dysregulation of metal homeostasis, and reduced abundance of virulence- and motility-associated proteins. We reported that PBT2 can act as a nickel ionophore, with Ni2+ being the highest-affinity ligand for PBT2 reported to date. Together, these findings suggest that PBT2 acts through a multifaceted, metal-dependent mode of action that limits the potential for emergence of resistance. Our work highlights PBT2 as a promising candidate for repurposing to treat multidrug-resistant H. pylori infections.IMPORTANCEAntibiotic resistance is steadily reducing our ability to treat common bacterial infections, while the development of new antibiotics has slowed. Helicobacter pylori is a clear example of this growing problem, with treatment failures becoming more common worldwide. This study highlights the value of taking a different approach by repurposing existing drugs for new antibacterial uses. Rather than acting on a single bacterial target, the compound examined here disrupts multiple essential processes at once, reducing the probability of resistance developing.

Quantitative characterization of vascular heterogeneity in complex microphysiological systems (MPS), particularly within patient-derived tumor microenvironments, remains a major challenge for scalable disease modeling and therapeutic evaluation. Existing analysis approaches primarily rely on vessel abundance-based morphometrics and often fail to resolve network connectivity and spatial remodeling in heterogeneous vascular systems. Here, we present the iMAP platform, a high-throughput digital vascular profiling framework that integrates an injection-molded microfluidic chip with an interactive image analysis tool (iMAP Analyzer). This platform enables topology-resolved and region-aware quantification of vascular architecture, capturing vessel morphology, branching complexity, connectivity, and spatial variation between tumor-proximal and distal regions. Applied to 3D co-cultures of patient-derived gastric cancer tumor spheroids with either donor-matched iPSC-derived endothelial cells (iPSC-ECs) or primary HUVECs, iMAP identified differences in network organization and spatial stability under standardized conditions, with iPSC-derived networks exhibiting increased fragmentation and peripheral instability. These findings demonstrate that connectivity-normalized and region-resolved analysis provides critical insight beyond conventional whole-image metrics. The iMAP framework offers a scalable and standardized approach for quantitative vascular phenotyping in complex MPS, supporting high-content analysis and advancing the development of vascularized in vitro disease models.

The epithelial-mesenchymal transition (EMT) transcription factor TWIST1 plays a critical role in breast cancer progression. This study reveals that TWIST1 acetylation, which is elevated in metastatic breast cancer tissues, is regulated by a deubiquitination-acetylation crosstalk. We demonstrate that ZRANB1 binds to and deubiquitinates TWIST1, thereby increasing its protein stability. This stabilization enhances the interaction between TWIST1 and the acetyltransferase ACSS2, leading to further TWIST1 acetylation. ACSS2 overexpression reversed ZRANB1 knockdown-induced inhibition of TWIST1 acetylation. Functionally, ZRANB1 overexpression promoted breast cancer cell proliferation, invasion, migration, and EMT in vitro, as well as lung metastasis in vivo, all of which were reversed by ACSS2 knockdown. Conversely, ACSS2 knockdown suppressed TWIST1 acetylation, EMT, and metastatic capabilities. Consistently, ACSS2 overexpression rescued the inhibitory effects of ZRANB1 knockdown on breast cancer cell viability, proliferation, migration, and invasion. In summary, our findings identify a novel regulatory axis wherein ZRANB1-mediated deubiquitination facilitates ACSS2-dependent acetylation to stabilize TWIST1, thereby driving EMT and metastasis in breast cancer. The ZRANB1/ACSS2 axis presents a promising therapeutic target for combating metastasis.

Gastric and colorectal cancers are common and deadly across the globe. Preclinical findings propose that the pairing of MET inhibitors with anti-inflammatory drugs could synergistically impede tumor growth and reshape the tumor microenvironment. This study introduces AspMet, a novel dual-targeting inhibitor of c-Met and COX-2. In vitro experiments demonstrated that AspMet significantly inhibited the proliferation of MKN45 (IC50 = 1.05 ± 0.02 nM) and SW480 (IC50 = 1.32 ± 0.01 μM) cell lines. The experimental data indicate that AspMet effectively blocks several cancer-promoting signaling pathways, including c-Met、TRKB、COX-2 and HIF-1α, significantly inhibits epithelial-mesenchymal transition, thus decreasing tumor cell migration and invasion, and causes DNA damage, resulting in G0/G1 cell cycle arrest and the initiation of apoptosis. Furthermore, AspMet has strong anti-angiogenic properties. In animal models, AspMet significantly reduced the growth of subcutaneous tumors in both gastric and colorectal cancers，and it has an extremely high bioavailability. Therefore, the dual inhibition strategy targeting c-Met and COX-2 offers a promising novel approach for the treatment of cancers, particularly inflammatory cancers.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterised by remarkable cellular heterogeneity, which emerges early from the interplay of oncogenic KRAS signalling and inflammatory injury. However, the transcriptional, metabolic and functional properties of these pre-malignant cell states that initiate and drive PDAC progression remain elusive. This study aimed to identify and functionally characterise the critical premalignant cell states that arise from this heterogeneity, to define novel biomarkers and targets for early intervention. Public and in-house scRNA-seq data of pancreatic tumour models were analysed to identify key subpopulations in early cellular heterogeneity. Genetic perturbation in KrasG12D-driven models was performed to assess functional impact. Mechanistic studies used TurboID proximity proteomics, epigenetic profiling and metabolic assays. Clinical relevance was validated in human PDAC cohorts. We identified LY6D as a marker of a distinct, gastric-like cell state that emerges early and persists throughout tumourigenesis. The LY6D+ population exhibits conserved stemness and a unique, pan-stage dependency on oxidative phosphorylation (OXPHOS). Genetic ablation of Ly6d specifically impaired the gastric lineage and delayed tumourigenesis, while its overexpression enhanced tumourigenic and metastatic potential. Mechanistically, the glycosylphosphatidylinositol (GPI)-anchored LY6D protein scaffolds a lipid raft-associated kinase network that drives FOSL1-dependent epigenetic-transcriptional reprogramming. In human PDAC, LY6D+ cells harbour stemness and Epithelial-Mesenchymal Transition (EMT) signatures, and high LY6D expression is an independent prognostic marker of poor survival. Our work defines the LY6D+ gastric-like cell state as a key driver linking early pre-malignant heterogeneity to PDAC initiation and progression. LY6D represents a pan-stage therapeutic target and a candidate biomarker for early detection and therapeutic targeting.

Incompletely understood mechanisms serve to maintain Epstein-Barr virus (EBV) latency, in which viral oncogene(s) are expressed, but lytic antigens are not expressed. Shortly after the discovery of EBV and even before it was named, Werne and Gertrude Henle identified that restriction of extracellular arginine induces EBV lytic antigens within Burkitt lymphoma tumor cells. However, for nearly 60 years, it has remained unknown how arginine metabolism supports EBV latency. To gain insights, we performed an amino acid restriction screen in EBV+ Burkitt cell lines. This confirmed that arginine restriction was sufficient to trigger EBV reactivation in Burkitt B cells and in gastric carcinoma models. Arginine restriction strongly impaired de novo pyrimidine biosynthesis, and CRISPR- or chemical genetic-blockade of pyrimidine biosynthesis enzymes induced EBV immediate-early and early lytic gene expression. However, arginine restriction blocked EBV lytic DNA replication and, consequently, also late gene expression, suggesting an abortive lytic cycle. By contrast, chemical or CRISPR blockade of the de novo pyrimidine biosynthesis pathway rate-limiting enzyme CAD reactivated a full EBV lytic cycle, suggesting specific arginine restriction roles in support of lytic DNA replication. Arginine restriction caused DNA damage, which was a driver of EBV reactivation. Arginine restriction and DNA hypomethylation additively reactivated EBV. Together, our results highlight arginine and pyrimidine metabolism as potential targets for EBV lytic antigen induction therapy in B-cell and epithelial-cell contexts. Altered metabolism is a hallmark of cancer, frequently increasing transformed cell dependence on extracellular amino acid supply. Despite current interest in Epstein-Barr virus (EBV) lytic antigen induction therapy, in which viral lytic reactivation sensitizes tumors to the highly cytotoxic effects of the antiviral ganciclovir, there has been no systematic study of extracellular amino acids that control EBV latency. We identified that arginine uptake was important for the maintenance of EBV latency in both Burkitt lymphoma and gastric carcinoma contexts. Metabolic pathway analyses highlighted that arginine uptake and metabolism were required to supply pyrimidines. Disruption of arginine metabolism or de novo pyrimidine synthesis caused DNA damage. Arginine restriction also triggered Burkitt DNA hypermethylation. Building upon this, we provide evidence that the combination of arginine restriction and DNA hypomethylation, either by decitabine or by CRISPR approaches, induced EBV reactivation more strongly than either alone, suggesting a therapeutic approach..

Protein therapeutics have garnered significant enthusiasm for oncological applications, owing to their exquisite specificity and intrinsic bioactivity. Yet, proteins remain constrained by limited transcellular permeability and proteolytic susceptibility during delivery. To circumvent these impediments, we engineered a redox-responsive protein prodrug, RP-ss-PK, via covalent conjugation of cytotoxic proteinase K (PK) to a multifunctional polymer, RGD-PEG-ss-NPC. This linear hetero-difunctional PEG scaffold contains a cyclic RGD peptide at the α-terminus for integrin-mediated tumor targeting and a 4-nitrophenyl ethyl carbonate (NPC) group at the ω-terminus for site-specific conjugation to amine-rich lysine residues on PK. An internal disulfide linker (-ss-) renders the prodrug cleavable in the presence of intracellular glutathione (GSH). Upon systemic administration, RP-ss-PK selectively accumulates within neoplastic lesions via RGD-integrin (αvβ3/αvβ5) recognition. Endocytosis exposes the disulfide tether to the cytosolic glutathione milieu, triggering reductive cleavage and subsequent liberation of native, fully active PK. The unleashed protease initiates indiscriminate proteolysis that precipitates rapid tumor cell death, accompanied by plasma-membrane permeabilization. This membrane disruption facilitates the extracellular release of damage-associated molecular patterns (DAMPs), thereby igniting anti-tumor immunity and remodeling the tumor microenvironment. Collectively, this prodrug paradigm not only amplifies the tumor-selective delivery of protein therapeutics but also exemplifies a facile, broadly applicable strategy for intracellular activation and functional restoration of protein cargos. Our findings establish RP-ss-PK as a versatile platform poised for the targeted protein treatment of diverse pathologies.

Liquid biopsy based on circulating microRNAs (miRNAs) holds great promise for cancer diagnosis and treatment monitoring. However, the development of detection methods that are sensitive, specific, cost-effective, and compatible with diverse biofluids remains a challenge. Here, we report a sensitive and label-free detection platform, termed SCAN (Split crRNA-Activated CRISPR/Cas12a and Amplification Network), that integrates split CRISPR/Cas12a with catalytic hairpin assembly (CHA) for isothermal miRNA analysis. In this design, the target miRNA, serving as an alterable spacer RNA (sRNA), assembles with a conserved repeat RNA (rRNA) to reconstitute a functional full-length crRNA, activating the trans-cleavage activity of Cas12a. This cleaves a blocker probe and releases an initiator strand, which subsequently triggers a CHA cascade. The CHA reaction generates abundant G-quadruplex (G4) structures that bind specifically to N-methylmesoporphyrin IX (NMM), yielding a strong turn-on fluorescence signal. The optimized "signal-on" model achieved a detection limit of 2 fM for miR-21, offering approximately 5 orders of magnitude higher sensitivity than the basic split CRISPR/Cas12a system. The platform exhibited excellent specificity, capable of single-base mismatch discrimination, and could be readily adapted for detecting miR-128, miR-27a, and miR-155 through simple exchange of the double-stranded DNA activator. Importantly, by employing the label-free G4/NMM reporter, the cost of the signaling module was reduced by more than 45-fold compared to conventional dual-labeled probes. The SCAN platform reliably quantified miR-21 overexpression in colon cancer cell lines and robustly differentiated plasma samples from patients with multiple cancer types (colorectal, lung, cervical, breast, and thyroid cancers) from healthy individuals. Furthermore, it demonstrated utility in tracking treatment response through noninvasive urine analysis in prostate cancer and bladder cancer. This work establishes a sensitive, specific, low-cost, and versatile biosensing platform for miRNA-based liquid biopsy, holding strong potential for clinical diagnostic applications.

Peritoneal carcinomatosis (PC) is an aggressive manifestation of advanced gynecological and gastrointestinal malignancies with high recurrence rates despite cytoreductive surgery and chemotherapy. We developed a cationic liposomal nanoparticle (DSTAP, ∼159 nm) to deliver and retain the toll-like receptor 7/8 agonist Resiquimod (R848) within the peritoneal cavity, aiming to modulate the tumor immune microenvironment (TIME) and improve therapeutic efficacy. DSTAP-R848 was evaluated in murine colorectal and ovarian PC models, alone or combined with oxaliplatin (Oxa). Survival, cure rates, and durable immunity following tumor rechallenge were assessed. Immune polarization was examined by incubating ascites and peritoneal fluid with naïve splenocytes, while flow cytometry and metabolomic profiling characterized intratumoral immune populations and metabolic changes. Combination therapy achieved cure rates of 80% in the colorectal model and 30% in the ovarian model, with no recurrence after rechallenge; Oxa monotherapy yielded no cures. Oxa+DSTAP-R848 increased CD8+ T cells and M1 macrophages, while reducing regulatory T cells and myeloid-derived suppressor cells. Immunosuppressive and glycolytic metabolites progressively declined, correlating with reduced tumor burden. Overall, DSTAP-R848 enhances chemotherapy efficacy by reshaping immune and metabolic pathways and promoting durable anti-tumor immunity in PC.

The evolution of drug-tolerant persister (DTP) cells into resistant clones remains a major clinical obstacle to targeted therapies. Transcriptomic profiling across melanoma (A375, SK-MEL-28), non-small cell lung cancer (NSCLC; HCC827, PC-9), and colorectal cancer (CRC; SW480) models revealed a conserved biphasic telomerase regulation during DTP evolution. Combining targeted therapies with the telomere dysfunction-inducing agent 6-thio-dG effectively suppressed DTP outgrowth and resistance in vitro and in vivo. Mechanistically, 6-thio-dG induces telomere dysfunction-driven chromatin remodeling, which reduces the accessibility of the SUCLG2 locus to transcription factors. The subsequent downregulation of this mitochondrial enzyme severely disrupts the metabolic stability required for DTP survival. Consistently, SUCLG2 knockdown recapitulated these therapeutic effects. Furthermore, bulk RNA sequencing (RNA-seq) of HCC827 xenograft-derived samples confirmed that this combination therapy coordinately suppresses mitochondrial metabolism, telomere maintenance, and persister transcriptional programs. Collectively, preemptively combining 6-thio-dG with targeted therapies offers a potent strategy to disrupt DTP evolution and overcome adaptive resistance across diverse malignancies.

Specific biomarker detection has become a pervasive diagnosis method across worldwide. Various research has focused on detection in buffer solution thereby resulting in the ignorance of such application in practical scenario. Thus, investigation for specific biomarker measurement in human body fluid is crucial for technology conversion. Graphene, this two-dimensional material with high conductivity and carrier mobility, has caught the researchers' attention in recent years. Herein, we present a graphene field effect transistor (GFET)-based aptameric nanobiosensor for rapid detection in biofluids incorporated with 4arm-PEG, with multiple-branched architecture providing terminal functional groups and maintaining strong hydration capability for effective resistance to nonspecific protein adsorption. CEA, a specific biomarker related to various diseases such as colorectal, gastric and lung cancer, was chosen as a representative tumor biomarker for experimental validation. The results indicate that this 4arm-PEG-modified graphene aptameric nanobiosensor generates a higher signal compared to the traditional rejection element as well as responds to CEA concentration change in a few minutes (3-5 min) with the estimated detection limits of 7.5aM in 1×PBS, 6aM in saliva solution, and 27aM in interstitial fluid solution, respectively. Hence, our sensor holds great potential for accurate monitoring nanomole levels in human body fluid among clinical applications.