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To evaluate the clinical applicability of previously established transcriptomic signatures (molecular subtypes, components and GemPred status) in metastatic pancreatic cancer, we conducted a retrospective pooled analysis of 178 patients from three phase 2 trials (PRODIGE35/37, AFUGEM; 2013-2016) testing first-line regimens (FOLFIRINOX, GemNab, FuNab, FOLFIRI3). RNA sequencing was performed on primary/metastatic tumors across French centers, with blinded assessment of subtypes (immune classical, pure basal-like, stroma-activated), quantitative components, and GemPred status. Primary endpoint: progression-free survival (PFS). Immune classical subtype showed superior median PFS (9.03 months) and OS (11.27 months) versus basal-like and stroma-activated subtypes (PFS: p=0.015; OS: p=0.010). Higher classical component correlated with improved PFS (HR=0.83, p=0.048) and OS (HR=0.71, p=0.001). Inactive stroma predicted better PFS (HR=0.64, p=0.001) and OS (HR=0.71, p=0.015). GemPred-negative patients treated with FOLFIRINOX versus GemNab had higher ORR (46.9% vs. 19.1%, p=0.046), longer PFS (8.2 vs. 2.3 months; HR=2.28, p=0.008), and OS (11.6 vs. 5.0 months; HR=2.04, p=0.021). No differences occurred in GemPred-positive patients. In a formal treatment-by-GemPred interaction analysis (FOLFIRINOX vs. GemNab), the interaction was significant for OS (adjusted p-interaction=0.050) but not for PFS (adjusted p-interaction=0.51). Transcriptomic signatures retain prognostic and predictive utility in metastatic pancreatic cancer, with GemPred representing a hypothesis-generating predictive signal for OS (e.g., a FOLFIRINOX OS benefit in GemPred-negative). Prospective validation is warranted for clinical implementation.

Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with limited prognostic biomarkers and therapeutic targets. Lactate-driven lactylation has recently emerged as an important regulator of cancer progression, but its role in PAAD remains unclear. In this study, integrative analysis of TCGA and GEO datasets, combined with experimental validation, identified a five-gene lactylation-associated signature (LRP3, TTLL6, TSGA13, PRKCG, and SDK2) that effectively stratified PAAD patients by survival risk. High-risk tumors displayed an immunosuppressive phenotype with reduced immune infiltration, Th2-skewed remodeling, checkpoint activation, and distinct mutational and drug-sensitivity features. Among the signature genes, PRKCG was significantly downregulated in PAAD and associated with advanced disease and worse prognosis. PRKCG overexpression inhibited tumor cell proliferation, migration, invasion, and xenograft growth, while enhancing apoptosis. Mechanistically, lactate-induced lactylation impaired PRKCG-dependent activation of the p53 pathway without altering PRKCG expression, and mutation of predicted lactylation sites partially rescued this effect. These findings define a lactylation-associated prognostic model for PAAD and highlight the lactate-PRKCG-p53 axis as a potential therapeutic vulnerability.

New-onset diabetes (NOD) increases the risk of pancreatic cancer. Previous studies have mainly focused on the presence or absence of diabetes, with limited attention to NOD severity at diagnosis and its clinical course. This 15-year longitudinal nationwide cohort study aimed to analyse the pancreatic cancer risk based on the initial severity and progression pattern of NOD. We included 402 663 individuals with or without NOD from the Korean National Health Insurance Service (2005-2019). Initial NOD severity was defined by baseline antidiabetic treatment intensity: no antidiabetics, oral antidiabetics and insulin. Pancreatic cancer risk increased stepwise with higher initial treatment intensity in NOD compared with individuals without diabetes (adjusted HRs (aHRs) 3.01, 4.32 and 5.60 for no antidiabetics, oral antidiabetics and insulin, respectively). Within the same baseline treatment-intensity category, individuals with rapid escalation within 6 months had a higher risk of pancreatic cancer than those with stable or decreased treatment intensity. In some comparisons between groups with different baseline treatment intensities, the risk of pancreatic cancer was higher with less intensive baseline therapy but subsequent intensification than with more intensive baseline therapy without progression. Notably, drug-naïve individuals who initiated antidiabetic treatment within 6 months had a greater risk even than those who were initially on oral medication without worsening (aHR 6.50 vs 3.67). These patterns were more prominent in pancreatic cancer cases diagnosed within 3 years after NOD. Greater initial severity of NOD and rapid early aggravation were both associated with an increased risk of pancreatic cancer.

Pancreatic cancer continues to be among the most lethal malignancies. The distinct tumor microenvironment (TME) not only facilitates tumor cell proliferation, invasion, and metastasis but also establishes a formidable barrier to the diffusion of chemotherapeutic agents and immunotherapies. Consequently, it is imperative to identify novel compounds that target the tumor microenvironment (TME). This study aims to identify a small molecule as a therapeutic agent for pancreatic cancer through dual mechanisms, specifically DDR1 inhibition and methuosis induction. We characterized DDR1 as a primary target of N-(4-Methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazol-1-yl)phenyl)-6-(trifluoromethyl)picolinamide (IHMT-140) using ADP-Glo assays, KINOMEscan, Western blotting, and molecular docking. Colony formation, invasion, wound-healing migration, and immunohistochemical staining assays demonstrated that IHMT-140 suppresses epithelial-mesenchymal transition (EMT) by regulating key EMT markers. Cell viability assays, including Cell Titer-Glo and live-cell imaging, transmission electron microscopy (TEM), and immunofluorescence staining, revealed that IHMT-140 triggers methuosis in pancreatic cancer cells. RNA-seq was also employed to confirm the underlying mechanisms. Finally, Cell Titer-Glo, Western blot, and flow cytometry were applied to demonstrate the combined antitumor effects of IHMT-140 and gemcitabine. Gemcitabine uptake and tumor accumulation were quantified by high-resolution mass spectrometry. The in vivo efficacy was tested in a xenograft model, with tumor sections analyzed by H&E and pan-collagen staining. We discovered N-(4-Methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazol-1-yl)phenyl)-6-(trifluoromethyl)picolinamide (IHMT-140) as a novel dual-function agent that acts as a DDR1 inhibitor and a methuosis inducer. It simultaneously remodels the tumor stromal ECM and activates excessive macropinocytosis. Pharmacological evaluation shows that IHMT-140 inhibits tumor invasion and metastasis, enhances gemcitabine accumulation in tumors, and significantly improves therapeutic outcomes. Our findings present a promising therapeutic strategy for pancreatic cancer, integrating DDR1 kinase inhibition with methuosis induction to augment chemotherapy efficacy. This approach provides a potential novel approach for pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133HighGSTT1High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1HighCD133High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.

Ferroptosis links cellular metabolism to immune regulation. Beyond its role as an iron-dependent form of regulated cell death, ferroptosis generates signals, including oxidized lipids, iron metabolites, and damage-associated molecular patterns, that influence inflammatory and immune responses. The pancreas is particularly susceptible to ferroptotic stress because of its high metabolic demand and close integration with immune and stromal networks. In pancreatitis, ferroptosis translates metabolic injury into innate immune activation, contributing to sterile inflammation and tissue damage. In pancreatic cancer, ferroptotic vulnerabilities can be exploited therapeutically, yet ferroptosis-associated signals may also support immune suppression, immune evasion, and treatment resistance. These findings suggest that ferroptosis functions as an immunometabolic checkpoint rather than simply a cell death program. Here, we discuss how ferroptosis shapes immune responses in pancreatitis and pancreatic cancer and examine the factors that determine whether it promotes inflammation, antitumor immunity, or immune tolerance. We also review ferroptosis-targeted therapies and the challenges associated with their clinical application.

Pancreatic ductal adenocarcinoma (PDAC) presents a substantial challenge due to its resistance to cancer treatments. This limited efficacy is, in part, attributed to the immunosuppressive tumor microenvironment (TME), which impairs effector T (Teff) cell activity. Interleukin-2 (IL-2) is a key cytokine for T cell activation, but its therapeutic use is limited by a short half-life, systemic toxicity, and regulatory T (Treg) activation. To address this limitation, we engineered Bifidobacterium longum, a probiotic obligate anaerobe that selectively colonizes the TME, to continuously secrete Super-mutant IL-2 (SumIL-2), an engineered IL-2 variant that preferentially activates Teff cells over Treg cells, thereby delivering SumIL-2 selectively to the tumor (BifidoSumIL-2). Systemic administration of BifidoSumIL-2 significantly suppressed tumor growth in both subcutaneous tumors and orthotopic PDAC in mice, inducing an improved Teff/Treg ratio. Combining BifidoSumIL-2 with chemotherapy, radiation, and immunotherapy further restrained orthotopic PDAC growth, highlighting its therapeutic potential for difficult-to-treat cancers like PDAC.

Despite advancements in therapeutic cancer vaccines, clinical translation has been hindered by limited efficacy, with Sipuleucel-T remaining the only FDA-approved therapeutic cancer vaccine to date. However, recent advances in personalized mRNA vaccines, such as Moderna's mRNA-4157 and BioNTech's autogene cevumeran, have demonstrated significant reductions in recurrence risk and improved survival across several cancer types, renewing optimism in the field. Personalized cancer vaccines leverage patient-specific tumor antigens to initiate potent and targeted immune responses. This review outlines various classes of personalized vaccines, including DNA-, mRNA-, peptide-, dendritic cell-, and whole-cell-based platforms, and examines the immunological challenges they face, such as tumor heterogeneity, immunosuppressive microenvironments, and inadequate immune memory. To address these limitations, both conventional and nanotechnology-enhanced delivery systems have been developed. Notably, nanovaccines constructed from lipid-polymer hybrids, biomimetic membranes, and stimulus-responsive materials enable codelivery of neoantigens and immunostimulatory agonists, promoting enhanced lymph node targeting, dendritic cell activation, and antigen cross-presentation. Furthermore, biomimetic formulations incorporating autologous tumor membranes preserve native antigenic diversity and allow dynamic adaptation to evolving tumors. When integrated with artificial intelligence for antigen selection and multiomics for patient stratification, these platforms accelerate vaccine design and improve precision. Combination regimens with immune checkpoint inhibitors or other agents further potentiate efficacy and promote durable antitumor immunity. Increasing clinical evidence, especially in melanoma and pancreatic cancer, underscores the potential of these strategies to induce long-term protection and reduce recurrence. Overall, next-generation personalized cancer vaccines are advancing the transition from reactive treatment to proactive, precision-controlled cancer immunotherapy.

Curative-intent surgery in patients with perihilar cholangiocarcinoma (pCCA) is associated with substantial surgical risks and high early-recurrence rates. This study aimed to develop an ABC system for preoperative staging of patients with pCCA. This retrospective international multicenter cohort study included patients with resected pCCA across 27 participating centers from 9 countries (2006-2022). The prognostic performance of the ABC system for overall survival (OS) and recurrence was assessed using multivariable (cause-specific) Cox regression. Among 1307 included patients (median age, 66 [IQR, 57 to 73] years), independent prognostic factors for OS were: tumor size ≥25 mm (adjusted hazard ratio [aHR], 1.32 [95% CI, 1.13 to 1.55]; P=0.0003), CA19-9 ≥500 U/mL (aHR, 1.49 [1.22 to 1.81]; P<0.0001), and WHO performance status ≥1 (aHR, 1.35 [1.12-1.63]; P=0.002). The ABC score for OS consisted of 1 point for each independent prognostic factor (0-3 points); the ABC score for recurrence did not include WHO PS ≥1 (0-2 points). Compared to the ABC-0 group, the highest ABC risk group had a 3.4 times higher 90-day mortality risk (21 vs 6%; P=0.005), a 3.3 times higher 6-month recurrence rate (18 vs 5%; P<0.0001), a 3.0 times shorter median OS (13 vs 39 months; P=0.0001), and a 3.6 times lower 5-year OS rate (11 vs 35%; P=0.018). The prognostic value of the ABC score for OS remained similar in a sensitivity analysis including only patients with a resection post-2015 (Pinteraction=0.90). Following the ABC system, we should be reluctant to offer resection to patients with an ABC score of 3 with a tumor size ≥25 mm, CA19-9 ≥500 U/mL, and a WHO PS ≥1.

Surgical resection is a cornerstone of curative therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), the two most common primary liver malignancies. In most patients with HCC, underlying cirrhosis is present, whereas in iCCA an identifiable risk factor is often absent. Regardless of tumour type, surgical planning must account for the future liver remnant to minimise the risk of post-hepatectomy liver failure, evaluating not only its volume but also its functional reserve. Furthermore, a deeper knowledge of surgical oncological principles combined with integrative strategies, including systemic and locoregional therapies, has enabled downstaging and conversion of initially unresectable liver malignancies, expanding surgical eligibility across a growing spectrum of hepatic tumoural conditions. Additionally, advances in the understanding of molecular biology and new treatment strategies, particularly in iCCA, have the potential to further extend the boundaries of resectability.

Common bile duct (CBD) injury is a rare but devastating complication of laparoscopic cholecystectomy. Intraoperative indocyanine green (ICG) fluorescence cholangiography may improve biliary visualization, but its effect on CBD injury has not been well demonstrated. To evaluate the association between intraoperative ICG use and CBD injury after laparoscopic cholecystectomy. This cohort study included data from multiple hospitals in the Epic Cosmos dataset for adult patients (18 years and older) undergoing laparoscopic cholecystectomy between 2016 and 2024. Robotic cases, surgery for hepatobiliary malignancies, planned open procedures, and patients with inadequate follow-up were excluded from analysis. Data were analyzed from November 2025 to January 2026. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding by indication. Intraoperative ICG fluorescence cholangiography. The primary outcome was CBD injury within 1 year of surgery. Secondary outcomes included subsequent biliary intervention within 1 year, conversion to open surgery, and rates of any nonbiliary postoperative complications within 30 days. A total of 1 266 024 patients were included for analysis, of whom 164 695 (13%) underwent indocyanine green cholangiography. Among them, 118 626 (72.0) were female and 46 069 (28.0) were male; the mean (SD) age was 51 (17) years. ICG use increased from 1143 patients (1.6%) in 2016 to 47 816 (26%) in 2024. After IPTW adjustment, ICG was associated with lower rates of CBD injury (408 [0.25%] vs 659 [0.40%]; relative risk [RR], 0.62; 95% CI, 0.49-0.79; P < .001), need for any subsequent biliary intervention (7387 [4.49%] vs 8902 [5.39%]; RR, 0.83; 95% CI, 0.77-0.90; P < .001), conversion to open surgery (657 [0.40%] vs 1386 [0.84%]; RR, 0.48, 95% CI, 0.40-0.56; P < .001), and nonbiliary complications at 30 days (11 939 [7.25%] vs 14 275 [8.64%]; RR, 0.84; 95% CI, 0.78-0.91; P < .001). In this large national cohort, intraoperative ICG use was associated with lower rates of CBD injury, fewer postoperative biliary procedures and nonbiliary complications, and reduced conversion to open surgery. These findings support the use of ICG to enhance biliary safety in laparoscopic cholecystectomy and demonstrate its utility in reducing CBD injury.