胆胰外科领域文献阅读汇编

Desmoplastic stroma defines pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. This stroma drives tumor progression, immune evasion, drug resistance, and poor drug delivery. Although targeting tumor stroma has shown preclinical promise, most clinical trials have failed due to limited translational success. A major hurdle is the stroma's extreme heterogeneity and dynamic nature, meaning uniform treatments fail. Emerging evidence supports the existence of distinct 'stromal states' with differential biological functions and therapeutic vulnerabilities. Characterizing these states provides a framework to stratify patients and guide precise, stroma-directed therapies. This review summarizes the clinical landscape of PDAC stroma-targeting strategies, discusses distinct stromal states, and outlines emerging opportunities to exploit the stroma as a therapeutic axis in PDAC to improve clinical trial outcomes.

Dense stromal barriers and lysosomal sequestration severely restrict the extracellular transport and intracellular trafficking of nanomedicines in pancreatic cancer, while the robust glutathione (GSH)-dependent antioxidant defense further compromises therapeutic efficacy. Here, we developed a proton sponge-enabled dual-driven nanomotor, HA/PEI-DOX@MMSN@Pt (HPDMP), for MRI-guided pancreatic cancer therapy. The asymmetric Pt domain generated near-infrared (NIR)-induced self-thermophoretic motion as the principal externally controllable driving mechanism, whereas endogenous H2O2 provided auxiliary catalytic propulsion, together facilitating nanomotor transport through the dense tumor stroma and enhancing intratumoral penetration. Following cellular uptake, PEI-mediated proton sponge activity facilitated lysosomal escape and increased cytosolic DOX availability. Meanwhile, tumor-microenvironment-responsive degradation of the Mn-doped framework consumed GSH and released Mn2+, thereby enhancing reactive oxygen species (ROS) generation, ferroptosis-associated oxidative damage, and T1-weighted MRI contrast. HA modification further promoted CD44-mediated tumor targeting. Under NIR irradiation, HPDMP achieved pronounced antitumor efficacy with favorable biosafety. This work provides a barrier-oriented nanomotor strategy for pancreatic cancer therapy.

Dietary interventions can influence cancer progression, yet the role of low-protein diets (LPDs) in pancreatic ductal adenocarcinoma (PDAC) immunotherapy is unclear. Here we show that an LPD suppresses PDAC progression in male mice by remodeling the gut microbiota and activating antitumor immunity. LPD promoted immune activation and drove an immunostimulatory tumor-associated macrophage phenotype. Microbiota depletion abolished these effects and fecal microbiota transplantation from LPD-fed donors transferred the protective phenotype to recipients. Mechanistically, LPD enriched Blautia coccoides, which produced uridine diphosphate (UDP)-galactose to activate the macrophage P2Y14R-STAT1 axis, inducing an immunostimulatory phenotype. Combining LPD, B. coccoides or UDP-galactose with anti-PD1 improved survival over anti-PD1 alone. In persons with advanced PDAC, reduced fecal B. coccoides and serum UDP-galactose correlated with poor outcomes. These findings establish that LPD reshapes the gut microbiota and metabolites to enhance antitumor immunity through the UDP-galactose-P2Y14R-STAT1 axis, offering a dietary strategy to improve PDAC immunotherapy.

Macroautophagy (MA) and chaperone-mediated autophagy (CMA) are lysosomal degradation pathways with context-dependent roles in cancer. However, how MA- and CMA-associated transcriptional states jointly relate to cancer molecular features and drug responses remains unclear. Here, we developed a transcriptome-based framework integrating MA- and CMA-associated gene signatures to define relative MA and CMA states across cancer types. These states were associated with distinct patterns of genomic instability, oncogenic signaling, immune features, and pharmacogenomic profiles. In pooled cancer cell-line analyses, MAhigh CMAhigh states were associated with relative resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), whereas MAhigh CMAlow states showed greater sensitivity, nominating an autophagy-associated pharmacological pattern for mechanistic investigation. Using KRAS-mutant pancreatic cancer cells as an autophagy-dependent, therapy-resistant model, we found that LAMP2A depletion enhanced sensitivity to EGFR-TKIs in an MA-dependent manner. All-trans retinoic acid (ATRA), a pleiotropic retinoid that modulated CMA-related activity in this system, phenocopied key effects of genetic CMA suppression and potentiated sensitivity to EGFR-TKIs. CMA suppression was associated with increased autophagic flux, TFEB nuclear localization, and ULK1 phosphorylation changes consistent with MA activation. Moreover, transcriptomic analysis reveals that CMA suppression sensitizes cancer cells to EGFR-TKIs at least partially through downregulation of SEMA6D. SEMA6D depletion enhanced autophagic flux, increased lysosomal capacity, and partially contributed to the response to combined EGFR-TKI and ATRA treatment. In PANC-1 xenografts, ATRA potentiated EGFR-TKI-mediated tumor suppression without significant toxicity. Together, these findings establish a transcriptome-based MA-CMA framework for prioritizing context-dependent autophagy-associated vulnerabilities and provide focused mechanistic support for MA-CMA crosstalk in KRAS-mutant pancreatic cancer models.

Pancreatic tumors are characterized by a prominent desmoplastic stroma that can account for up to 90% of the tumor. Given the marked upregulation of CD44, a family of transmembrane glycoproteins, in pancreatic cancer-associated fibroblasts (CAFs), we investigated its role in regulating myofibroblastic and inflammatory CAF phenotypes. Conditional deletion of Cd44 in fibroblastic cells in Cd44fl/fl;PdgfrβCreERT2 mice significantly reduced tumor growth and was associated with a significant reduction in intratumoral regulatory T cells (Treg). Consistently, in human CAFs CRISPR/Cas9-edited to delete CD44, the fibroblasts' morphology changed drastically: CAFs lost their elongated phenotype and adopted a round shape, reflecting their inactivation. This was accompanied by a significant downregulation of activation markers, unresponsiveness to exogenous stimuli, and reduced contractile activity. Furthermore, CD44 ablation decreased extracellular matrix production and altered the immunomodulatory cytokine secretion, highlighting its role in both fibrosis and immune regulation. Finally, CD44-deficient CAFs exhibited a reduced capacity to suppress anti-tumor immune responses by failing to induce immunosuppressive programs in dendritic cells (DCs) and by increasing cytotoxic T cell (CTL)-mediated tumor cell killing. Collectively, we identify CD44 as a regulator of CAF activation and immunosuppressive function, linking stromal remodeling to immune evasion in pancreatic cancer and supporting CD44 as a potential therapeutic strategy to reprogram the tumor stroma and enhance anti-tumor immunity.

Pancreatic ductal adenocarcinoma (PDAC) relies on elevated autophagy to support metabolism, proliferation, and immune evasion. Inhibiting autophagy has been reported to improve response rates in patients with PDAC. In this work, we identified a mechanism to explain how the loss of autophagy in PDAC triggers reprogramming of the tumor microenvironment (TME) to ultimately stimulate an antitumor response. Autophagy inhibition in PDAC recruited macrophages via the CXCL1/2-CXCR2 axis. Simultaneously, the loss of autophagy resulted in a decrease in the canonical "don't eat me" ligand CD47 on tumor cells, thereby inducing their susceptibility to macrophage phagocytosis. Although CD8+ T cells were critical to the antitumor immune response to autophagy inhibition in PDAC, they were not directly involved in cytotoxicity but played a critical role in stimulating macrophage phagocytosis of tumor cells. Taken together, this study strongly supports the implementation of autophagy inhibition in pancreatic cancer and highlights a crucial link between PDAC biology and the TME-macrophage cross-talk that effectively promotes tumor cell killing. Inhibition of autophagy in pancreatic cancer promotes antitumor immunity through a stepwise process of recruiting macrophages and enhancing phagocytosis of cancer cells, providing a potential therapeutic strategy for this deadly tumor type.

Pancreatic cancer remains one of the deadliest malignancies, with gemcitabine-based chemotherapy as the mainstay treatment for most patients, yet resistance emerges almost universally. A defining feature of pancreatic cancer is its dense, fibroblast-rich stroma, in which heterogeneous cancer-associated fibroblasts (CAF) actively shape tumor biology and therapeutic response. Here, we elucidated a stromal-metabolic mechanism through which chemoresistant CAFs confer gemcitabine resistance. We identified a subset of mitophagy-competent CAFs that enhanced pancreatic cancer gemcitabine resistance. The epithelial-mesenchymal transition transcription factor ZEB1 acts as a master regulator of this CAF-driven chemoresistance program, being upregulated and epigenetically activated via SETD1A-mediated H3K4 methylation in gemcitabine-resistant CAFs. ZEB1 promotes BNIP3-mediated mitophagy in CAFs, leading to increased nucleotides secretion, which competitively inhibited gemcitabine incorporation into cancer cells while simultaneously supplying pyrimidine metabolism substrates for pyrimidine metabolism. Concurrently, ZEB1 transcriptionally activated CXCL8, engaging the CXCR1/2-MEK/ERK pathway in tumor cells and further augmenting pyrimidine metabolism via the RRM1/E2F1/G6PD axis, collectively diminishing gemcitabine cytotoxicity. Notably, combined inhibition of CXCR1/2 or G6PD with gemcitabine robustly suppressed tumor growth and restored chemosensitivity both in vitro and in vivo. These findings uncover a key stromal-metabolic axis in pancreatic cancer, linking mitophagy CAF activity to metabolic remodeling in tumor cells and identifying ZEB1 and its downstream network as actionable targets to overcome chemoresistance. ZEB1 reprograms mitophagy-competent CAFs to promote gemcitabine resistance by enhancing nucleotide supply and activating tumor pyrimidine metabolism, supporting therapeutic targeting of the ZEB1-CXCL8-pyrimidine axis in pancreatic cancer.

The lethality of pancreatic ductal adenocarcinoma (PDAC) is driven, in part, by cellular plasticity that facilitates dedifferentiation and dissemination. Although transcriptional programs underlying these processes are well characterized, the contribution of translational control to PDAC cell-state regulation in vivo needs to be further understood to develop strategies to restrain malignant plasticity. Using a genome-wide CRISPR/Cas9 screen in immunocompetent hosts, we identified the noncanonical initiation factor eIF4G2 (DAP5/NAT1) as a translational checkpoint that restrains PDAC progression. Loss of eIF4G2 accelerated tumor growth, promoted poorly differentiated, basal-like histology, and triggered widespread metastasis. Ribosome profiling revealed that eIF4G2 supports the translation of a discrete cohort of mRNAs with long, guanine-cytosine (GC)-rich, structured 5' untranslated regions, including tumor suppressors such as Pten and transcriptional regulators such as Crebbp. Accordingly, loss of eIF4G2 was accompanied by secondary transcriptional enrichment of migration and wound-healing programs and induction of basal-like markers. In human PDAC, eIF4G2 expression was reduced in poorly differentiated lesions, and functional eIF4G2 perturbation in patient-derived PDAC cells increased clonogenic growth, whereas enforced eIF4G2 expression suppressed colony formation. Computational inference from human PDAC datasets revealed that reduced eIF4G2 activity correlated with increased metastasis, enhanced basal-like features, and poorer patient survival. Together, these findings establish noncanonical translation initiation as a determinant of PDAC cell-state control and identify eIF4G2 as a barrier to malignant plasticity and metastatic dissemination. The translational checkpoint regulator eIF4G2 preserves epithelial identity and suppresses metastasis in pancreatic cancer, revealing selective translation as a determinant of subtype, prognosis, and therapeutic stratification.

The Tn antigen, a truncated O-glycan, is frequently elevated in pancreatic ductal adenocarcinoma (PDAC). Multiple therapeutic approaches targeting Tn have been developed, but they have not demonstrated clear efficacy signals in early phase clinical studies. Improving Tn-targeted strategies in PDAC will require both overcoming the immunosuppressive tumor microenvironment and defining pathways by which truncated O-glycans promote growth and immune evasion. Here, we showed that Tn reshapes the tumor immune landscape of PDAC. Expression of Tn antigen on PDAC cells enhanced proliferation in vitro and tumor growth in vivo. Tn expression remodeled the immune microenvironment, skewing tumor-associated macrophages toward M2-like phenotypes, reducing cross-presenting dendritic cells, and expanding myeloid-derived suppressor cells (MDSCs). Single-cell RNA sequencing confirmed expansion of MDSCs and downregulation of antigen processing and presentation in the immune cell infiltrate of Tn+ tumors. Tumor-intrinsic transcriptomic analyses revealed activation of TNF-α/NF-κB signaling and induction of IL-34, a cytokine linked to monocyte survival and differentiation in Tn antigen expressing tumors. Additionally, high Tn expression in both organoids derived from pancreatic cancer patients and in PDAC mouse models was associated with increased IL-34 expression. Genetic deletion of Il34 in PDAC cells attenuated Tn-driven tumorigenesis and reduced MDSC infiltration, while recombinant IL-34 promoted myeloid cell differentiation and proliferation in vitro. Together, these findings establish a glyco-immune-cytokine axis in which truncated O-glycans contribute to IL-34-mediated immunosuppression, providing mechanistic insight and potential therapeutic targets in PDAC.

The poor prognosis of cholangiocarcinoma (CCA) is largely driven by rapid, asymptomatic disease progression, which usually results in a late diagnosis in the absence of established screening strategies. An early, cost-effective, and universally applicable risk assessment strategy would therefore be valuable. We developed machine learning (ML) models on prospective, multimodal data from 487,495 UK Biobank (UKB) participants, of whom 649 developed CCA during follow-up. Data from England (80%) were utilised for ML development via five-fold cross-validation, and then all models were tested on withheld data from Scotland, Wales, and Newcastle (20%). Iterative ablation studies reduced inputs from >150 features across demographic data, lifestyle, health records, blood parameters, genomics, and metabolomics to models built on five and ten routinely available clinical parameters. These were externally validated in the Penn Medicine Biobank (PMBB; n = 2638; 28 CCA), All of Us Research Program (AOU; n = 330,433; 362 CCA), Japan Medical Data Centre Claims Database (JMDC; n = 8,425,522; 723 CCA) and TriNetX (n = 728,886; 1592 CCA). We show that ML models integrating biliary-disease associated health records and Gamma glutamyltransferase can stratify risk of future CCA. Evaluation on the UKB test set as well as three independent cohorts revealed robust performance and generalisability across ethnicities. We achieved AUROCs of 0.71 [95% CI: 0.703-0.711], 0.77 [95% CI: 0.764-0.778 ], 0.796 [95% CI: 0.795-0.798] and 0.8 [95% CI: 0.794-0.805] for UKB, PMBB, AOU, and JMDC respectively, with respective AUPRCs of 0.014 [95% CI: 0.009-0.018], 0.042 [95% CI: 0.037-0.048], 0.038 [95% CI: 0.033-0.042] and 0.001 [95% CI: 0.001-0.001]. In AOU, application of the Youden J-optimised threshold yielded a number needed to screen of 79. Separate models for intra- and extrahepatic CCA did not improve performance. In line with the pathophysiology, performance declined for longer intervals between assessment and event. A group-level analysis in the TriNetX cohort revealed hazard ratios of up to 82.5 [95% CI: 26.4-257.96]. We provide extensive interpretability results and release all source codes used to develop the presented models. We provide a comprehensive framework for early CCA risk stratification in the general population, identifying key predictors, and demonstrating the potential of data-driven models in personalised screening for hepatobiliary cancer. German Cancer Aid (grant #70115730), Junior Principal Investigator Fellowship programme of RWTH Aachen Excellence strategy.

Photodynamic therapy (PDT) has been shown to improve survival and quality of life in patients with unresectable extrahepatic cholangiocarcinoma. However, its therapeutic efficacy is frequently limited by the survival of residual tumor cells that can re-enter the proliferative cycle. Our previous studies showed that residual cholangiocarcinoma cells can re-enter the proliferative cycle following PDT accompanied by hypoxia-induced activation of the HIF-1α survival pathway and intracellular antioxidant programs. To address this residual viability, we developed a glutathione-responsive targeted nanosystem (TSH NPs), in which the aggregation-induced emission (AIE) photosensitizer TPA-Ph-RDN is conjugated to the chemotherapeutic agent hydroxycamptothecin (HCPT) via a disulfide linkage. This design enables HCPT to exert direct cytotoxic effects while simultaneously suppressing the HIF-1α-mediated hypoxic adaptation pathway, thereby reducing residual tumor viability and enhancing PDT efficacy. This strategy achieves a dual-mechanism, two-pronged therapeutic effect. Both in vitro and in vivo studies demonstrated that TSH NPs elicited markedly synergistic antitumor activity, highlighting their potential as a promising therapeutic approach for improving clinical outcomes in patients with eCCA.

KRAS mutations are a major driver of pancreatic ductal adenocarcinoma (PDAC). RASA2, a RAS GTPase-activating protein, modulates KRAS protein levels in wild-type contexts, suggesting it could play a potential role in PDAC. Here, we systematically investigated the biological function and molecular mechanisms of RASA2 in PDAC. Integrative analyses of multiple datasets and clinical samples demonstrated that RASA2 was consistently upregulated in KRAS-mutant PDAC and significantly associated with poor prognosis and metastatic progression. Gain- and loss-of-function studies revealed that RASA2 markedly enhanced PDAC cell migration and invasion in both KRAS-mutant and KRAS-wild-type models, suggesting that its pro-metastatic activity is largely independent of KRAS mutational status. Transcriptomic and mechanistic analyses revealed that RASA2 activated GLI1 through a TGFβ2-dependent, non-canonical Hedgehog pathway. Mechanistically, RASA2 interacted with RTF1 to promote H2BK120 ubiquitination at the TGFB2 promoter, thereby enhancing TGFβ2 transcription and activating downstream GLI1 signaling. Pharmacological inhibition of TGFβ signaling or genetic silencing of GLI1 effectively suppressed RASA2-driven migratory, invasive, and metastatic phenotypes in vitro and in vivo. Collectively, these findings reveal a mechanism by which RASA2-dependent epigenetic and transcriptional reprogramming promotes metastatic progression and nominate the RASA2- TGFβ2-GLI1 axis as a potential therapeutic target in PDAC.

Chimeric antigen receptor (CAR) T-cell therapy has shown limited efficacy in solid tumors, largely due to immunosuppressive mechanisms within the tumor microenvironment (TME). While tumor-associated glycans are known to protect malignant cells from immune attack, the contribution of N-glycans expressed by non-malignant TME populations to CAR-T cell dysfunction remains poorly defined. We investigated the role of N-glycans in non-malignant TME populations, focusing on M2-like macrophages and hepatic stellate cells in liver metastasis of colorectal (CRC) and pancreatic cancer (PDAC). Using in vitro co-culture systems, transcriptomic analysis, and tumor-bearing humanized mouse models, we assessed how pharmacologic or genetic disruption of key nodes of the N-glycosylation pathway (MGAT5, MAN2A1 and ST6GAL1) in immune and stromal compartments shapes T-cell function. In patient samples, a branched N-glycan signature was associated with transcriptional programs characteristic of tumor-promoting macrophages and stromal cells, linking N-glycosylation to an immunosuppressive TME. Disruption of N-glycan synthesis in non-malignant TME cells reduced their immunosuppressive and tumor-supporting functions. Single-cell RNA sequencing of tumor-bearing humanized mice showed depletion of protumor IL1β+ macrophages and diminished inhibitory macrophage-T cell interactions following N-glycosylation blockade. Selective MGAT5 disruption in immune and stromal compartments suppressed immunosuppressive programs and enhanced CAR-T cell antitumor activity independently of tumor cell glycosylation. These findings show that N-glycans expressed by non-malignant TME cells restrain CAR-T cell responses in CRC and PDAC, highlighting MGAT5-dependent branching as a potentially actionable axis and supporting a broader role for multiple nodes of the N-glycosylation pathway.

Ischemia-reperfusion (I/R) is a common and unavoidable phenomenon during surgeries such as hepatectomy and liver transplantation, severely affecting patient prognosis. However, clinically intervention and treatment measures remain very limited. Using human hepatocyte organoid hypoxia-reoxygenation (H/R) and murine hepatic ischemia-reperfusion (I/R) models, we demonstrate that the microbiota-derived flavonoid desaminotyrosine (DAT) attenuates I/R-induced hepatic injury by suppressing inflammation and apoptosis while promoting the abundance of probiotic Bifidobacterium in the gut. Through integrated spatial transcriptomics and metabolomics, we identified that DAT specifically alters the MAPK signaling pathway/ ferroptosis gene transcriptome in the portal vein (PV) zones, promotes the production of antioxidants (taurine) in the central vein (CV) zones, reduces the level of pro-ferritinosis substrates (arachidonic acid), thereby enhancing the expression of GPX4 and Nrf2, inhibiting ferroptosis, then ameliorate hepatic I/R injury. Meanwhile, the pseudo-germ-free mouse model confirmed that DAT alleviated hepatic I/R injury in a gut microbiota dependent manner. DAT reduces hepatic I/R injury by increasing the abundance of gut Bifidobacterium pseudolongum (Bif). Our research results reveal a novel microbial metabolite that improves hepatic I/R injury, clarify the inhibitory effect of DAT on ferroptosis, discover new therapeutic uses of DAT, and identify Bif as a potential novel probiotic for preventing liver I/R injury, providing new options for the preventive treatment of liver I/R injury.