胃肠外科领域文献阅读汇编

Anbenitamab (Ennituo®), a bispecific IgG monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), is being developed by Alphamab Oncology for the treatment of various solid tumours (including gastric cancer and breast cancer). Anbenitamab received its first approval in China on 27 May 2026. Anbenitamab, in combination with chemotherapy, is approved for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received at least one trastuzumab-containing therapy. This article summarizes the milestones in the development of anbenitamab leading to this first approval for gastric or GEJ cancer.

Cancer-associated fibroblasts (CAFs) foster an immunosuppressive tumor microenvironment (TME) and confer resistance to immune checkpoint blockade (ICB) in gastric cancer (GC). However, the mechanisms by which specific CAF subsets regulate metabolic crosstalk and immune evasion remain poorly defined. We integrated bulk and single-cell RNA-sequencing data, spatial transcriptomics, and clinical cohorts of GC patients treated with immunotherapy. Functional validation was performed using in vitro co-culture systems, multiple murine models, and lipid nanoparticle (LNP)-encapsulated siRNA targeting Postn. We identified POSTN + CAFs as a key subset enriched in ICB non-responders and associated with poor prognosis. Mechanistically, POSTN secreted by CAFs engaged integrin β1 (ITGB1) on tumor cells and macrophages, activating the PI3K/AKT/mTOR signaling axis and upregulating PPARγ. This signaling cascade drove lipid metabolic reprogramming, characterized by increased lipid accumulation and oxidative stress, and promoted the polarization of macrophages toward an immunosuppressive, lipid-stressed M2 phenotype. Targeting POSTN signaling with LNP-formulated siPostn attenuated tumor growth, suppressed lipid metabolism, and reduced M2 macrophage infiltration in the TME. This work reveals that POSTN + CAFs establish an immunosuppressive TME and are associated with ICB non-response in GC by remodeling lipid metabolism through the ITGB1-PI3K/AKT/mTOR-PPARγ axis, a finding that underscores the therapeutic value of intervening in this specific CAF-macrophage metabolic crosstalk.

Gastric cancer (GC) derives limited benefit from immunotherapy, with clinical responses observed in only a minority of patients. Increasing evidence suggests that heterogeneity within the tumor immune microenvironment (TME) is a critical determinant of immunotherapeutic efficacy, highlighting the need for precise immune stratification and the identification of molecular biomarkers that shape the TME. We integrated single-cell transcriptomic data from our cohort and public datasets to characterize immune microenvironment heterogeneity in GC. Functional experiments were performed using in vitro assays and in vivo mouse models to investigate the molecular mechanisms regulating immune exhaustion. Clinical relevance was evaluated using tumor specimens from patients with GC receiving anti-programmed cell death protein 1 (PD-1) therapy. Survival analyses and biomarker evaluation were conducted to assess the prognostic and predictive value of candidate markers. We identified two distinct GC immune microenvironment subtypes: the immunosuppressive (GC1) and the immune-activated (GC2). PRKX was identified as a key regulator associated with immune heterogeneity and exhaustion. Clinically, a high density of PanCK+ PRKX+ PD-L1+ tumor cells was significantly associated with poor prognosis and served as a robust biomarker predicting 5-year survival in patients treated with anti-PD-1 therapy. Mechanistically, PRKX phosphorylates programmed death-ligand 1 (PD-L1) at T285, promoting YWHAE recruitment and preventing UBE2M-mediated ubiquitination and degradation, thereby stabilizing PD-L1 protein. Through this phosphorylation-dependent regulation of PD-L1 stability, PRKX suppresses CD8+ T-cell cytotoxicity, promotes immune exhaustion, and limits the efficacy of anti-PD-1 therapy in vivo. Therapeutically, lipid nanoparticle-mediated delivery of PRKX-targeting siRNA effectively suppressed PRKX expression and synergized with anti-PD-1 therapy to enhance antitumor efficacy. PRKX drives immune exhaustion in the GC1 subtype by stabilizing PD-L1 through phosphorylation-dependent inhibition of ubiquitination, thereby promoting immune evasion. Targeting PRKX represents a potential strategy to overcome resistance to anti-PD-1 therapy, and PRKX expression may serve as a prognostic biomarker to guide immunotherapy in GC.

Recurrence and peritoneal metastasis remain major challenges in gastric cancer (GC), highlighting the need to identify actionable stromal-tumor signaling circuits within the tumor microenvironment (TME). Integrated transcriptomic analyses and clinical validation identified TAGLN as a fibroblast-enriched factor associated with GC progression and poor prognosis. Functional studies showed that TAGLN expression in cancer-associated fibroblasts (CAFs) enhanced HGF production, at least in part through NF-κB activation, thereby promoting GC-cell malignant phenotypes via paracrine HGF/c-MET signaling. Mechanistically, HGF/c-MET activation promoted DDX5 phosphorylation, with Tyr595 identified as a critical phosphorylation site, and increased DDX5 nuclear accumulation. Nuclear DDX5 was enriched at the CAV1 promoter and enhanced CAV1 transcription, whereas CAV1 promoted malignant phenotypes by activating the PI3K/AKT/mTOR signaling. Salvianolic acid A (SA-A) showed TAGLN target engagement in DARTS and CETSA assays and attenuated TAGLN-associated CAF activity. In vivo, SA-A suppressed CAF-driven tumor growth and peritoneal dissemination. Collectively, these findings define a CAF-TAGLN/HGF/c-MET/DDX5/CAV1 signaling cascade linking stromal activation to tumor-cell transcriptional reprogramming and CAF-tumor crosstalk within the TME, and identify TAGLN as a potential therapeutic vulnerability for microenvironment-directed intervention in GC.

First-line treatment for gastric cancer (GC) includes PD-1 blockade with chemotherapy, but resistance challenges treatment success. We identify Streptococcus anginosus (SA) as a tumor-resident oncobacterium driving GC progression and immune evasion. SA is enriched in GC patient tumors and drives tumor growth in mice. SA extracellular vesicles (saEVs) translocate the bacterial chromatin remodeler saSNF2 into host cells. saSNF2 partners with host transcription factor TEAD1-through its ATPase activity and participation in BRG1/BRM-associated factor (BAF) complex assembly-to activate oncogenic transcription. This transkingdom interaction upregulates the palmitoyltransferase ZDHHC11, which stabilizes PD-L1 via palmitoylation to establish an immunosuppressive niche, while amplifying other TEAD1 target genes to fuel tumor progression. saEVs promote tumor growth and limit CD8+ T cell infiltration in vivo. Pharmacological inhibition of ZDHHC11 reverses immune evasion and synergizes with anti-PD-1 checkpoint blockade. These findings establish SA as a multifaceted driver of GC and highlight the saSNF2-ZDHHC11 axis as a target to potentiate immunotherapy.

Gastric cancer (GC) is one of the most common malignancies worldwide and it is the third leading cause of cancer-related death in China. While Helicobacter pylori is a known GC pathogen, its abundance declines in tumours and the role of other bacteria in GC metastasis remains unclear. We aim to investigate the mechanisms of other bacteria influencing GC progression and metastasis. Integrated intratumoural microbiome-metabolome analysis identified GC-associated microbes and metabolites. We then demonstrated the pro-metastatic role of Acinetobacter baumannii (A. baumannii, Ab) and its metabolite nicotinic acid (NA) using genetic, molecular and in vivo approaches. The abundance of A. baumannii was significantly increased in GC tissues, correlating with advanced tumour stage and intratumoural NA levels. Fluorescence in situ hybridisation confirmed its colonisation in GC tumours. In co-culture systems, A. baumannii increased NA levels, enhancing nicotinamide adenine dinucleotide (NAD) metabolism and increasing 1-Methylnicotinamide accumulation in tumour cells. Mutagenesis of the bacterial NA synthase gene pncA confirmed that A. baumannii excreted an NA-dependent pro-metastasis effect. Mechanically, A. baumannii promotes GC metastasis by reprogramming tumour cell glucose metabolism, reducing oxidative phosphorylation while enhancing glycolysis and activating the hypoxia-inducible factor-1 pathway in GC cells through metabolites both in vivo and in vitro. This study elucidates the role of A. baumannii in enhancing NAD metabolism in GC cells through NA synthesis, consequently promoting GC metastasis. These findings establish a microbiota-metabolism axis as a mechanistic foundation for developing targeted therapeutic strategies against GC metastasis.

The purpose of this review is to highlight areas in which digital technologies including mobile apps, wearables, telehealth, and AI have improved obesity care, where gaps remain, and future directions. Technology is being used in myriad ways to support lifestyle, pharmacological, and surgical obesity care. Mobile apps and wearables reduce the burden of behavior change strategies (e.g., self-monitoring) and telehealth eliminates numerous barriers to in-person obesity care. However, low engagement is a persistent problem with digitally-delivered interventions. An emerging area is the use of AI in obesity care to glean personalized insights from data collected by wearables and mobile apps and to deliver lifestyle coaching. Technology increases access to obesity care, facilitates personalized care, and reduces burden. Future research should examine ways to improve engagement, to design adaptive interventions that are responsive to patients' evolving care needs, and to facilitate implementation in healthcare settings.

This review evaluates obesity as the organizing exposure linking mechanical loading and adipose-tissue dysfunction with tendon pathology. It synthesizes site- and outcome-specific human evidence, candidate mechanisms, tendon xanthomas associated with familial hypercholesterolemia (FH), and implications for targeted assessment and management. Human studies associate obesity and related cardiometabolic abnormalities with tendinopathy, tendon rupture, and postoperative outcomes, but findings vary by exposure, site, and outcome and remain predominantly observational. Limited human tissue and predominantly preclinical studies support candidate roles for glycation, oxidized lipids, chronic inflammation, mitochondrial and redox dysfunction, and impaired repair, although their causal sequence and human relevance remain uncertain. Recent single-cell and spatial studies reveal tendon cellular heterogeneity but have not established obesity- or metabolism-specific endotypes. Recurrent, bilateral, atraumatic, or treatment-resistant manifestations have been proposed as features of a hypothesis-generating "metabolic tendon phenotype" rather than a validated diagnostic entity. FH-related tendon xanthomas represent a distinct manifestation of severe cumulative low-density lipoprotein cholesterol exposure. Standard tendon-directed rehabilitation remains central, whereas tendon-specific benefits of cardiometabolic optimization, glucagon-like peptide-1 receptor agonists, bariatric surgery, or lipid-lowering therapy remain unconfirmed. The proposed mechanometabolic continuum integrates obesity-associated systemic influences with local loading as a conceptual framework rather than a validated disease model or screening tool. Current evidence does not support universal cardiometabolic or cardiovascular screening based on nonspecific tendinopathy alone; targeted assessment may be considered in selected patients with relevant clinical cues or conventional risk factors. Longitudinal human studies and intervention trials are needed to clarify causality and clinical utility.

This review summarizes obesity-induced adaptations in subcutaneous and visceral white adipose tissue (WAT) depots and discusses how incretin-based pharmacotherapies and bariatric surgery may influence WAT remodeling beyond weight loss, drawing on evidence from animal models and human studies. In obesity, adipose tissue undergoes pathological remodeling characterized by structural and cellular changes, extracellular matrix (ECM) remodeling, altered endocrine signaling, and impaired mitochondrial function that contribute to metabolic comorbidities. Weight-loss interventions, including incretin-based therapies and bariatric surgery, are associated with improvements in adiposity and metabolic outcomes, and multiple studies suggest accompanying changes in inflammatory, mitochondrial/thermogenic, and endocrine pathways within WAT; however, mechanistic evidence in humans remains heterogeneous and is often limited by tissue accessibility and study design. This review highlights candidate cellular and molecular mechanisms through which incretin-based pharmacotherapies and bariatric surgery may modulate WAT plasticity, emphasizing convergent and distinct effects across depots and the need for more longitudinal, tissue-level human studies to define weight-dependent remodeling versus changes not fully explained by weight loss.

Obesity is an established risk factor for postmenopausal hormone receptor-positive breast cancer, largely through estrogen-mediated pathways. Emerging evidence suggests that obesity-related metabolic dysfunction may also contribute to the risk and aggressive biology of receptor-negative breast cancer, particularly TNBC, among premenopausal women and populations undergoing rapid metabolic transition. This review evaluates epidemiologic, mechanistic, and translational evidence linking metabolic dysfunction to TNBC. Observational studies and pooled analyses report modest but reproducible associations between adiposity and TNBC, stronger in some metabolically high-risk populations but heterogeneous across studies. BMI-based Mendelian randomization generally yields inverse associations with overall breast cancer, whereas bariatric-surgery studies suggest lower overall incidence without establishing TNBC-specific effects. These discordant causal-inference findings do not demonstrate that obesity directly causes TNBC. Mechanistic studies indicate that adipose inflammation, adipokine imbalance, insulin/IGF-1 signaling, and immune remodeling can promote inflammatory signaling, metabolic adaptation, and epithelial plasticity. These processes support biologic plausibility but do not demonstrate de novo conversion to a receptor-negative subtype in vivo. Current evidence supports a model in which obesity-related metabolic dysfunction may create a breast microenvironment favoring tumor-promoting inflammation and aggressive features associated with TNBC. Priorities include refined metabolic phenotyping, biomarker-driven risk stratification, validation in human-relevant models, and biomarker-enriched feasibility studies testing whether modifying metabolic dysfunction alters intermediate metabolic or tissue endpoints. An evidence-graded framework is needed to distinguish association, biologic plausibility, and causal inference.

Accurate prediction of pathological complete response (pCR) following neoadjuvant therapy is crucial for personalized treatment planning in patients with locally advanced rectal cancer (LARC). This study aimed to explore the application of 3D transrectal ultrasound (TRUS) for this purpose. In this study, 538 LARC patients from five hospitals were enrolled and divided into training (n = 348), internal validation (n = 87), and external validation (n = 103) cohorts. Using pretreatment 3D TRUS data of the rectal tumors, a deep learning framework comprising an automated segmentation model and a pCR prediction model was constructed and validated. The segmentation model achieved an excellent Dice score of 0.89. The predictive model, when trained on data sampled at 9° or 18° intervals, yielded area under the curve (AUC) values of 0.92 (internal validation) and 0.85-0.86 (external validation), with accuracies of 86.2%-90.8% and 81.6%-83.5%, respectively; decision-curve analysis also demonstrated clinically meaningful net benefits. This study presents the first deep learning framework based on 3D TRUS for pCR prediction in LARC patients, offering an automated and reproducible tool that may support clinical decision-making in rectal cancer management. However, further validation in larger, multi-device cohorts is essential before clinical application.

Gastric cancer (GC) displays marked heterogeneity under the Lauren classification, yet the metabolic determinants of subtype divergence remain unclear. Here, we identify Malonyl-CoA:ACP transacylase (MCAT), a Lauren subtype-associated gene encoding a key mitochondrial fatty acid synthesis (mtFAS) enzyme, as a subtype-specific tumor suppressor in GC. Integrative multi-omics profiling revealed that MCAT expression is enriched in intestinal-type GC and correlates with favorable prognosis. Mechanistically, MCAT overexpression drives metabolic reprogramming through mitochondrial free fatty acid overload, suppressing β-oxidation while elevating mitochondrial reactive oxygen species (ROS), which triggers P53 phosphorylation at Ser15. This event concurrently activates PINK1/Parkin-mediated mitophagy and suppresses the SLC7A11/GPX4 axis to induce ferroptosis. Genetic rescue experiments confirmed that P53-Ser15 phosphorylation is essential for both mitophagy and ferroptosis induction. Endogenous MCAT levels are sufficient to determine basal ROS/P53/mitophagy/ferroptosis axis activity, and knockdown in high-expressing cells reverses these phenotypes, supporting a physiological, threshold-dependent role. In vivo, MCAT overexpression suppresses tumor growth and enhances mitophagy and ferroptosis markers. Collectively, these findings establish MCAT as a metabolic switch that links mtFAS to ROS/P53-dependent cell death, providing a potential biomarker and therapeutic target for GC.

Peritoneal metastasis is a leading cause of mortality in end-stage gastric cancer and remains poorly responsive to conventional chemotherapy. To address this unmet need, Janus dendron-modified phthalocyanines were developed as tumor-targeted photosensitizers for photodynamic therapy (PDT). A series of Janus dendron-modified phthalocyanines with tailored surface functionalities s synthesized, exhibiting spontaneous self-assembly into nanoparticles with augmented fluorescence, amplified reactive oxygen species (ROS) production, and improved tumor-targeting specificity. Among them, the lead compound TT1-4PYR, bearing pyrrolidone moieties, demonstrated ascites-derived protein corona and macropinocytosis-mediated cellular internalization, enabling deep penetration and selective accumulation in peritoneal metastasis lesions. Comprehensive evaluation in vitro, in vivo, and in human-derived gastric cancer organoid models confirmed its potent and targeted photodynamic cytotoxicity, effectively suppressing tumor progression without inducing systemic toxicity, achieving a favorable biosafety profile. These results highlight TT1-4PYR as a promising and deep-penetrating therapeutic agent for peritoneal metastasis, with potential applicability to other metastatic malignancies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Epidemiological evidence indicates that MASLD is associated with an increased risk of developing colorectal cancer (CRC). MASLD and CRC share many common risk factors and pathophysiological mechanisms, but an optimal strategy for identifying and managing CRC risk in individuals with MASLD remains lacking. This study aimed to achieve consensus on the risk of CRC in individuals with MASLD. A Delphi survey was conducted by a multidisciplinary panel of 35 international experts from diverse medical fields across Asia, Europe, North America, South America, Oceania and Africa. Experts evaluated 17 statements across three domains: epidemiology, pathogenesis and management. Consensus was achieved on all 17 statements. MASLD is associated with an increased risk of CRC, and metabolic burden further increases this risk. Furthermore, the severity of MASLD is associated with worse outcomes in patients with MASLD and CRC. The gut-liver axis and gut dysbiosis play key roles in the development of MASLD and CRC, while leptin and adiponectin may also be involved. Weight loss with lifestyle interventions, early CRC screening, bariatric surgery and use of GLP-1 receptor agonists are highlighted as potential risk-reduction strategies. The expert panel emphasises the need for greater clinical vigilance for CRC among individuals with MASLD. This consensus supports a paradigm shift towards earlier, risk-adapted screening and integrated metabolic management to reduce the burden of CRC in the MASLD population.