INTRODUCTION:Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most malignant gastrointestinal tumors. M1 macrophage, a subtype within the Tumor Microenvironment (TME), plays a vital role in the development of cancer. Despite its anti-tumoral functions, the specific mechanisms of its action remain incompletely understood. METHODS:The effect of M1 macrophages on the proliferation ability and cell viability of PDAC cells was evaluated by Cell Counting Kit-8 (CCK-8) cell proliferation assay, cell clone formation assay, and flow cytometry. Western blot, qRT-PCR, confocal microscope, RNA-sequencing, and transmission electron microscope were performed to assess lipid peroxidation and ferroptosis level of PDAC cells in the context of M1 macrophage or TNF-α. RESULTS:M1 macrophages inhibited cell proliferation and promoted cell death of PDAC cells, in which ferroptosis played a vital role. Mechanistically, Tumor Necrosis Factor-alpha (TNF-α) released by M1 macrophages binds to the TNFR1 receptor on pancreatic cancer cells, activating the p38 MAPK signaling, which upregulates Acyl-CoA Synthetase Long-chain family member 4 (ACSL4) expression, a critical lipid metabolism enzyme linked to ferroptosis, thereby promoting ferroptosis. Knockdown of ACSL4 or TNFR1 significantly reduced TNF-α-induced ferroptosis. DISCUSSION:TNF-α is a major inflammatory cytokine and is mainly generated by macrophages and T lymphocytes. It is involved in many pathological processes, such as inflammatory diseases, autoimmune diseases, and cancer. Studies have shown that the administration of recombinant TNF-α can induce tumor regression in mice with sarcomas. In our study, systemic injection of TNF-α slowed the tumor growth in nude mice, but with no significant difference compared with the control group, which may partially be attributed to its angiogenic activity. TNF-α signals via two distinct membrane-binding receptors, TNFR1 and TNFR2, which regulate various diseases. In pancreatic cancer, the role of TNF-α is complex and poorly understood. In a previous study, they found that exogenous systemic administration of human TNF-α, which interacted with murine TNFR1, significantly increased overall tumor growth in the Panc02-PDAC model. Intriguingly, the loss of TNFR1 led to an impediment of immune cell infiltration into the tumor and impaired immunosurveillance, which accelerated tumor growth. This suggests that TNFR1 exerts both protumoral and anti-tumoral functions in the Panc02-PDAC model, but the overall outcome is likely dependent on the spatiotemporal availability of TNF-α. However, systemic TNF-α injection can lead to severe side effects in animals, limiting its further application. In a recent study, TNFR2 was found to promote tumorigenesis and progression in the KPC-PDAC model. Knockdown of TNFR2 or pretreatment with an anti-TNFR2 antibody could significantly slow the tumor progression and incidence. In our study, TNFR2 was found to have a low expression in pancreatic cancer cells and was barely detected with the failure of knockdown. However, the cell lines used in the former study were established from a KPC mouse model, while our experiments were conducted using human PDAC cell lines. Contrary findings are possible as cell lines originate from two different species. However, we will further investigate the mechanism of this difference. CONCLUSION:In summary, this study revealed that M1 macrophages could induce ferroptosis in pancreatic cancer cells through secreting TNF-α, indicating a potential therapeutic option for PDAC.

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.

In recent years, neoadjuvant therapy (NAT) has received growing interest and is now the standard of care for borderline resectable (BR) pancreatic cancer (PC) and locally advanced (LA) PC. Despite the proven benefits of both NAT and adjuvant therapy (AT), a critical question remains: whether patients undergoing pancreatectomy after NAT still benefit from additional adjuvant chemotherapy. In this systematic review and meta-analysis, we aimed to answer that question and explore potential subgroups and regimens that increase or decrease a potential survival advantage. A comprehensive systematic literature search was performed. The primary outcome measure was overall survival (OS), expressed as hazard ratios (HRs). HRs and their corresponding 95

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies of the digestive system, with a 5-year survival rate of only 13%, which is largely due to late-stage diagnosis and limited therapeutic options. Emerging evidence indicates that the gut microbiota has a critical role in PDAC tumorigenesis, progression, and therapeutic response. This review comprehensively summarizes current insights into gut microbiota-PDAC interactions, highlighting microbial alterations across taxonomic, functional, and clinical dimensions. Gut dysbiosis, which is marked by depletion of beneficial species and enrichment of pathogenic taxa, contributes to carcinogenesis through chronic inflammation, immune dysregulation, and metabolic reprogramming. In particular, the loss of butyrate-producing bacteria reduces anti-inflammatory activity and weakens CD8 + T cell function, thereby promoting tumor development. In addition to initiation, the gut microbiota also shapes PDAC progression through direct translocation to pancreatic tissue and systemic regulation of the tumor microenvironment (TME), influencing immune cell dynamics and fostering therapeutic resistance. Clinically, distinct microbial signatures are emerging as potential diagnostic and prognostic biomarkers. Moreover, microbiota-targeted interventions, including probiotics, synbiotics, fecal microbiota transplantation (FMT), metabolite supplementation, and dietary modulation, show promise as adjunctive therapeutic strategies. However, significant challenges remain in defining causal mechanisms and translating these findings into practice. Future research should integrate multi-omics profiling with well-designed clinical trials to delineate the gut microbiota-PDAC interaction network, guide precision microbiota-based interventions, and ultimately enable earlier detection and personalized treatment of this lethal disease.

BACKGROUND:The survival benefit of adjuvant chemotherapy (AC) for pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and resection remains controversial. Previous studies often pooled diverse disease stages or chemotherapy regimens, potentially obscuring regimen-specific outcomes. We sought to investigate the association of AC with overall survival (OS) among patients with resected borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), stratified by specific neoadjuvant and adjuvant regimens. METHODS:This multinational, retrospective cohort study included 834 patients with BRPC/LAPC who underwent curative-intent resection following NAT with either FOLFIRINOX or gemcitabine plus nab-paclitaxel (Gem/Nab). Propensity score matching (1:1) was utilized to minimize selection bias. The primary outcome was OS, analyzed using Kaplan-Meier methods and Cox proportional hazards models. RESULTS:Among 834 patients, 605 received neoadjuvant FOLFIRINOX and 229 received neoadjuvant Gem/Nab. In the matched analysis for the neoadjuvant FOLFIRINOX cohort, continuation of adjuvant FOLFIRINOX was associated with longer OS compared with no AC (median OS, 42.0 vs. 25.8 months; HR, 0.58; 95% CI, 0.43-0.79; p < 0.001). In contrast, switching to adjuvant Gem/Nab did not confer a survival benefit in this group (HR, 0.84; 95% CI, 0.61-1.15; p = 0.27). For patients receiving neoadjuvant Gem/Nab, adjuvant Gem/Nab or other regimens was not associated with improved OS (HR, 0.92; 95% CI, 0.64-1.34; p = 0.69). CONCLUSIONS:Survival benefits of adjuvant chemotherapy in resected BRPC/LAPC may be regimen-dependent. Postoperative continuation of FOLFIRINOX appeared to be associated with a survival advantage, whereas regimen de-escalation or adjuvant chemotherapy following neoadjuvant Gem/Nab demonstrated no clear benefit.

4198 Background: In China, gemcitabine (G) and nab-paclitaxel (nP) remain the standard first-line (1L) therapy for patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC). Our previous report (Wang W, et al; 2025 ASCO) showed that the add-on of surufatinib (S, multi-kinase inhibitor) and KN046 (K, bi-specific PD-L1/CTLA-4 antibody) to GnP chemotherapy provided enhanced anti-tumor activity in advanced PDAC. Here we present the updated results and findings from a biomarker analysis. Methods: In this single-arm, phase 1b/2 trial (NCT05832892), eligible pts with treatment-naïve advanced PDAC received oral S (200~250 mg, once daily), intravenous K (5 mg/kg, on day 1) and GnP (G 1000 mg/m 2 , nP 125 mg/m 2 , on days 1 & 8) at 21-day cycles till disease progression or intolerable toxicity. The primary efficacy endpoint was ORR per RECIST 1.1; secondary endpoints included DCR, PFS, OS and safety; efficacy-predictive biomarkers were exploratory endpoints. Results: Overall, 31 pts were enrolled with a median age of 56 years (range 40–74) and a predominant male gender (74.2%). Distant metastasis was present in 28 (90.3%) pts and 24 (77.4%) had liver metastasis (LM) at baseline. Best overall responses included 4 CR, 18 PR, and 6 SD. The ORR was 71.0% (95% CI 52.0–85.8) and DCR was 90.3% (95% CI 74.2–98.0). As of Dec 25, 2025, with a median follow-up of 15.9 months, median PFS was 8.2 months (95% CI 6.1–not estimable [NE]). Median OS was 18.0 months (95% CI 13.8–NE) with a 12-month OS rate of 68.2% (95% CI 50.8–91.6). Baseline LM was correlated to significantly worse PFS (8.0 vs NE months, log-rank P = 0.02), though no significant impact on ORR (73.9% vs 62.5%, P = 0.66), DCR (91.3% vs 87.5%, P = 1.00) or OS (13.8 vs NE, log-rank P = 0.12) was observed. Among the 27 pts who received ≥4 cycles of treatment, 22 (81.5%) and 19 (70.4%) experienced a decline in CA199 and CA125 from baseline, respectively, while fewer (37.0%) had CEA declined. A ≥50% decline in CA199 was correlated to significantly improved PFS (10.3 vs 8.1 months, log-rank P = 0.01) and a trend towards improved OS (NE vs 11.1 months, log-rank P = 0.11), as compared to a milder decrease or increase in CA199; Such correlation was not observed for CA125 or CEA. Treatment-related adverse events (TRAEs) occurred in 29 (93.5%) pts, of whom 14 (45.2%) experienced Grade ≥3 events, with hypertension (12.9%), neutropenia (12.9%), and thrombocytopenia (9.7%) being the most frequently observed. No treatment-related serious adverse events or deaths occurred. Conclusions: S plus K and GnP demonstrated consistently encouraging efficacy and manageable safety in 1L treatment of advanced PDAC. Early and sharp decline in CA199 may predict more favorable survival benefit. Analyses in genetic profile and its impact on clinical outcome will be carried out in future, and investigations in larger population are warranted. Clinical trial information: NCT05832892 .

Histopathological hematoxylin and eosin (H&E) slides contain valuable prognostic information for pancreatic ductal adenocarcinoma (PDAC), yet systematic feature extraction remains challenging. This multi-center study developed and validated an automated prognostic model using deep learning on digitized whole-slide images from 873 PDAC patients with surgical resection across three academic centers. The CrossFormer architecture achieved superior performance in external validation (area under the curve [AUC] = 0.774), significantly outperforming ResNet-18 (AUC = 0.716), ResNet-50 (AUC = 0.737), and DenseNet-121 (AUC = 0.729). Gradient-weighted Class Activation Mapping identified key prognostic features including desmoplastic stroma, high nuclear-to-cytoplasmic ratio, tumor necrosis, and immune cell infiltration. The pathomics signature effectively stratified patients into low-risk and high-risk groups with significant survival differences (p < 0.001). Critically, carbohydrate antigen 19-9 (CA19-9) retained prognostic value only in low-risk patients (hazard ratio [HR] = 2.70, p < 0.001) but not in high-risk patients (HR = 0.998, p = 0.990). High-risk patients derived substantial benefit from adjuvant chemotherapy (HR = 0.56, p = 0.038), whereas low-risk patients showed no significant benefit (HR = 0.83, p = 0.562). These findings provide actionable clinical insights: treatment intensification for high-risk patients and CA19-9-guided monitoring for low-risk patients. This validated, interpretable model transforms routine H&E slides into quantitative prognostic tools, enabling personalized treatment strategies without additional testing costs.

Circadian rhythms orchestrate 24-h oscillations in gene expression to govern diverse physiologic functions. Mounting evidence suggests that circadian disruption, resulting from aberrant light exposure, shift work, or genetic mutations in core clock genes (e.g., BMAL1 and PER2), promotes tumorigenesis and progression by dysregulating proliferation, apoptosis, cell cycle progression, metabolic reprogramming, and senescence. Critically, the circadian clock exerts spatiotemporal control over the tumor microenvironment, a dynamic ecosystem central to metastatic efficiency. This review synthesizes emerging mechanisms underlying circadian regulation of tumor microenvironment (TME) components during the metastatic cascade: 1) extracellular matrix (ECM) dynamics. Circadian oscillation of matrix metalloproteinases remodels collagen alignment at invasive edges. 2) Stromal crosstalk. Rhythmic secretion of cytokine by cancer-associated fibroblasts or macrophages gates intravasation efficiency on circulating tumor cells. 3) Immune-extravasation axis. Diurnal variations in endothelial adhesion molecules (ICAM-1/VCAM-1) regulate CTC extravasation, synchronized with neutrophil infiltration peaks. In this review how circadian perturbations (e.g., jet lag-induced cortisol spikes or CRY1 knockout) alter cytokine networks (TGF-β/IL-6), hypoxia responses, and metabolic symbiosis within the TME were dissected. This work unveiled chronotherapeutic targets to disrupt metastasis timing by integrating recent single-cell RNA-seq and intravital imaging data. However, details regarding the molecular mechanisms underlying TME have not been established. We anticipate that upcoming research will deepen our comprehension of these complex interactions, facilitating the creation of novel strategies for cancer therapy.

BACKGROUND:Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is constitutively expressed in barrier cells such as endothelial cells and fibroblasts. While the expression of IL-33 in regulatory T cells (Tregs) has been previously reported, its clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aims to investigate the clinical relevance and biological role of IL-33 + Tregs in PDAC. METHODS:Infiltration of IL-33 + Tregs was assessed by immunohistochemistry in 215 patients from our institute. The correlation between IL-33 + Tregs and clinical characteristics was analyzed. Additionally, the functional status of cytotoxic T cells in relation to IL-33 + Treg infiltration was examined. The impact of IL-33 + Tregs on the tumor microenvironment (TME) was further evaluated both in silico and in vitro . RESULTS:IL-33 + Tregs infiltration was confirmed in PDAC tissues, and its abundance was positively associated with microvascular invasion, perineural invasion, and elevated serum CA19-9 levels. Patients with higher tumor-infiltrating IL-33 + Tregs demonstrated poorer overall survival (OS) and recurrence-free survival (RFS) compared to those with lower infiltration levels. Multivariate analysis confirmed IL-33 + Tregs as an independent prognostic factor for both OS and RFS, with improved survival prediction when combined with tumor differentiation. Subgroup analyses indicated that serum CA19-9 was not a useful risk stratification tool in patients with high IL-33 + Treg infiltration, and these patients showed limited survival benefit from adjuvant chemotherapy. Furthermore, increased IL-33 + Treg infiltration was associated with more pronounced immunosuppressive TME, marked by a reduction in cytotoxic phenotypes and an upregulation of exhausted markers on CD8 + T cells. CONCLUSION:Our findings identify IL-33 + Tregs as a novel subtype of Tregs, with strong prognostic value for survival risk stratification and therapeutic response prediction in PDAC. IL-33 + Tregs exhibit more pronounced immunosuppressive capabilities, impairing CD8 + T cell function. With further investigation, IL-33 + Tregs may represent a promising immunotherapeutic target for PDAC.

As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domain-containing 7 (FBW7) inhibited the migration and proliferation of pancreatic cancer cells through its substrate c-Myc. We further found that another key substrate of FBW7, KLF5, could inhibit ferroptosis. Inhibiting KLF5 significantly enhances the cytotoxicity of oxaliplatin rather than other chemotherapy drugs. Mechanistically, we found that KLF5 inhibited the expression of heme oxygenase 1 (HMOX1) via repressing zinc finger E-box-binding homeobox 1 (ZEB1). Inhibition of KLF5 facilitated the cytotoxic effect of oxaliplatin via promoting ferroptosis. Oxaliplatin combined with KLF5 inhibitor significantly potentiated cell death in vitro and inhibited tumor growth in vivo compared with either treatment alone. These results reveal a critical role of KLF5 in sensitized chemotherapy of pancreatic cancer, and suggest that ferroptosis combined with platinum-based chemotherapy rather than gemcitabine-based chemotherapy is expected to bring better therapeutic effects.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, necessitating approaches to improve prognosis. As the mediator of allergic process, mast cells have been found in various cancers and are associated with survival. However, the biological behaviors of tumor-associated mast cells (TAMCs) remain unclear. Herein, an excessive infiltration of TAMCs in PDAC is demonstrated, which apparently associated with poor survival in PDAC patients. PDAC cells are found to recruit CXCR2+ MCs into TME, and then inhibited MCs ferroptosis, and maintained their proliferation. Concomitantly, the tumor-derived exosome miR-188-5p activated the PTEN/AKT/GSK3β signaling, further stabilized transcriptional factor ERG by inhibiting its ubiquitin degradation, and finally enhanced the transcription of cxcl10 within TAMCs. In reverse, TAMCs-derived CXCL10 reversely promoted tumor epithelial-mesenchymal transition and induced immunosuppressive tumor microenvironment by recruiting CXCR3+ Tregs. Sodium cromoglycate (SCG) is a membrane stabilizer for MCs and confirmed as an effective and widely used agent to block TAMCs-derived CXCL10 and further sensitize the therapeutic efficacy of anti-PD-1 antibody plus gemcitabine for PDAC. These findings illuminate a critical and innovative crosstalk between TAMCs and PDAC cells that promote PDAC progression, and SCG sensitizes PDAC to the current immuno-chemotherapy, which reveals its potential to be a valuable adjuvant for PDAC patients.

Neutrophils are essential components of the innate immune system. Tumor-associated neutrophils (TANs) are shaped by tumor microenvironment (TME), leading to significant heterogeneity in biological characteristics and functions. Recent advances in single-cell sequencing have revealed a wide array of TAN subtypes, while a comprehensive classification system is still lacking. This review aims to summarize the alterations observed in TAN subgroups following cancer immunotherapy, and identify the distinctions and commonalities between pro-tumor and anti-tumor subgroups. Current progress of preclinical and clinical studies is also highlighted, involving novel therapies targeting TANs.

PURPOSE:Pancreatic ductal adenocarcinoma (PDAC), known for its high fatality rate, is often diagnosed in its advanced stages where surgical options are not viable. This highlights the critical need for innovative and effective early detection techniques. This study focuses on the potential of cell-free DNA (cfDNA) fragmentomics integrating advanced machine learning to identify early-stage PDAC with high accuracy. METHODS:Our study included a broad cohort of 1,167 participants, from which plasma was collected and subjected to shallow whole-genome sequencing. After rigorous quality assessments, 166 individuals diagnosed with PDAC and 167 healthy participants were in the training cohort, whereas the validation cohort consisted of 112 patients with PDAC and 111 healthy individuals. A separate group of 67 individuals with nonmalignant pancreatic cysts was also included to validate the model's accuracy. Finally, two additional external validation cohorts and one additional independent early-stage data set were included to evaluate the robustness of model. Our analysis used fragmentomic profiling, integrating copy-number variations, fragment size, mutational signatures, and methylation patterns analyzed using machine learning. RESULTS:The model demonstrated remarkable accuracy in distinguishing patients with PDAC from controls, with an AUC of 0.992 in the training data set and 0.987 in the validation data set. At a cutoff of 0.52, the training set reached a sensitivity of 93.4% and a specificity of 95.2%. In the validation data set, the sensitivity was 97.3% with a specificity of 92.8%, while the external data set demonstrated a sensitivity of 90.91% and a specificity of 94.5%. CONCLUSION:This study underscores the effectiveness of using cfDNA fragmentomics and machine learning for early detection of PDAC. Our approach promises significant potential in reducing PDAC mortalities through early intervention and could serve as a breakthrough in oncologic diagnostics.

Background:. Limited knowledge and guidelines exist for invasive intraductal papillary mucinous neoplasm (IPMN). This study aims to explore the significance of lymph node involvement on adjuvant chemotherapy (ACT) for invasive IPMN. Materials and methods:. Patients diagnosed with invasive IPMN were selected from both the Surveillance, Epidemiology, and End Results (SEER) database and our hospital. Kaplan-Meier analysis, Cox proportional hazards model, and propensity score matching (PSM) were used in this study. Results:. In the SEER group, multivariate analysis involving 775 patients revealed that several factors including age, tumor differentiation, the American Joint Committee on Cancer (AJCC) T staging, N staging, and tumor node metastasis classification (TNM) stage significantly influenced overall survival (OS) and cancer-specific survival (CSS). Turning to the Zhongshan Hospital group (ZS group), which had 94 recruited patients, multivariate analysis for OS, CSS, and recurrence-free survival (RFS) showed that AJCC N staging emerged as the most significant risk factor, with hazard ratio (HR) values of 4.664, 4.955, and 3.175, respectively. In subgroup analysis, ACT provided survival advantages for patients with positive lymph node metastasis (LNM). In a PSM analysis focused on patients with positive LNM, the comparison revealed that ACT emerged as a critical factor influencing both OS and CSS (both P < .005). Especially, these patients younger than 60 years old or those with AJCC-T2-N+ staging were found to get apparently benefit from ACT as revealed by our subgroup interaction analysis. Conclusion:. LNM plays a pivotal role in the management of invasive IPMN patients who underwent surgery, and ACT might be a beneficial therapeutic option for individuals concurrent with LNM, particularly among those younger than 60 years old, or with AJCC-T2-N+ staging.

4157 Background: Gemcitabine (G) and nab-paclitaxel (nP) are standard 1L regimen for patients (pts) with unresectable PC, yet the efficacy remains unsatisfactory. K is a humanized bispecific antibody targeting PD-L1/CTLA-4, while S is a kinase inhibitor of VEGFR1-3, FGFR1 and CSF-1R with immune-regulatory potential. It is hypothesized the add-on of S and K to GnP chemotherapy would provide improved efficacy. Methods: This single-arm, phase 1b/2 trial enrolled pts with unresectable locally advanced or metastatic PC who were eligible for 1L treatment. The phase 1b part was designed in a "3+3" algorithm to determine the recommended phase 2 dose (RP2D) of S for dose expansion in phase 2 part. Pts received oral S at escalating dose starting from 200 mg qd, plus intravenous K at 5 mg/kg on day 1, and GnP chemotherapy on days 1 and 8 at 21-day cycles. The primary endpoint was dose-limiting toxicities (DLTs) within the first 28 days for phase 1b, and ORR per RECIST 1.1 for phase 2. Secondary endpoints included DCR, PFS, OS, safety, and efficacy-related biomarkers. Results: As of Dec 19th, 2024, 18 pts were enrolled with a median age of 54 (range: 41-74), predominantly male (16/18) and metastatic disease (15/18). Of the 16 pts with genetic testing, KRAS (15/16) and TP53 (11/16) mutations were common, followed by DNA damage response (DDR) -related mutations (7/16) including ARID1A , ATM , CHEK2 , etc., while TMB-H (1/16) is rare, and none had MSI-H or dMMR status. Within the 9 pts from phase 1b part (3 in S 200 mg cohort, 6 in S 250 mg cohort), no DLTs occurred thus the RP2D of S was determined as 250mg qd. In the 16 evaluable pts, the best overall responses were 1 CR, 10 PRs and 5 SDs. The ORR was 68.8% and the DCR was 100%. 2 pts received R0 resection after 6 cycles' treatment. With a median follow up of 7.43 months, the estimated median PFS was 8.25 (95% CI: 4.57-NR) months and the 6-month PFS rate was 72.9%. Estimated median OS was 11.14 (95% CI: 5.52-NR) months and the 6-month OS rate was 82.5%. In the exploratory analysis, DDR-related mutations seemed predictive for better ORR (85.7% vs 55.6%, P = 0.308), PFS (6-month PFS rate:100% vs 53.3%, log-rank P = 0.519), and OS (6-month OS rate:100% vs 62.5%, log-rank P = 0.116). Treatment-related adverse events (TRAEs) occurred in 14 (77.8%) pts, and most common TRAEs (≥20%) included leucopenia (44.4%), hypertension (38.9%), and thrombocytopenia (22.2%). TRAEs of grade ≥3 included leucopenia, neutropenia, thrombocytopenia, and hypertension (n = 2 [11.1%] for each). There were no treatment-related deaths. Conclusions: These preliminary results showed encouraging anti-tumor efficacy and an acceptable safety profile of S plus K and GnP chemotherapy as 1L treatment for advanced PC. Clinical trial information: NCT05832892 .

The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, facilitating tumor cells to develop invasive traits and augmenting their migratory capabilities. EMT is primed by tumor microenvironment (TME)-derived signals, whereupon cancer cells undergoing EMT in turn remodel the TME, thereby modulating tumor progression and therapeutic response. This review discusses the mechanisms by which EMT coordinates TME dynamics, including secretion of soluble factors, direct cell contact, release of exosomes and enzymes, as well as metabolic reprogramming. Recent evidence also indicates that cells undergoing EMT may differentiate into cancer-associated fibroblasts, thereby establishing themselves as functional constituents of the TME. Elucidating the relationship between EMT and the TME offers novel perspectives for therapeutic strategies to enhance cancer treatment efficacy. Although EMT-directed therapies present significant therapeutic potential, the current lack of effective targeting approaches—attributable to EMT complexity and its microenvironmental context dependency—underscores the necessity for mechanistic investigations and translational clinical validation.

Tumor‐intrinsic programmed cell death 1 (PD‐1) has been shown to activate the mesenchymal epithelial transition factor (MET) pathway via its phosphorylation in pancreatic ductal adenocarcinoma (PDAC). However, the immunoregulatory consequences of MET activation remain poorly understood. Herein, a significant positive correlation between phosphorylated MET (p‐MET) and tumor‐intrinsic PD‐1 is verified, both of which are independently associated with adverse prognosis. Elevated p‐MET levels correlated with diminished CD8 + T cell cytotoxicity and increased regulatory T cell (Treg) infiltration. Single‐cell RNA sequencing revealed MET activation selectively drives the accumulation of intratumoral GITR⁺ Tregs—a distinct effector Treg subset with potent immunosuppressive function and high prognostic relevance. Compared to KLF2⁺ naïve Tregs, GITR⁺ Tregs exhibited an activated phenotype and enhanced expression of immunoregulatory markers. Subgroup analysis further demonstrated that elevated GITR⁺ Treg infiltration diminished the prognostic utility of serum CA19‐9, underscoring the immunosuppressive dominance of this Treg subset. Mechanistically, MET–IL‐23–STAT4 axis orchestrates GITR⁺ Treg‐mediated immune evasion in PDAC. In vivo, MET inhibition and GITR agonism synergize to enhance antitumor immunity in an orthotopic PDAC model. Collectively, these findings highlight MET signaling and GITR⁺ Tregs as actionable targets to counteract immune evasion and improve the efficacy of immunotherapeutic strategies in PDAC.

BACKGROUND:Surgery remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), which has remarkably high morbidity and mortality rates. However, recurrence is prevalent after resection. The effectiveness of circulating tumor DNA (ctDNA) in recurrence prediction has been demonstrated, and methylation has advantages over traditional biomarkers in terms of early-stage specificity. These advances indicate the need for a ctDNA-based methylation marker for PDAC prognosis, which would be valuable in clinical practice. METHODS:MIR129-2 promoter methylation markers were identified via a combination of differential methylation, differential expression, gene set enrichment analysis and survival analysis using TCGA data. A qPCR-based assay was developed to quantify MIR129-2 methylation in plasma samples with as little as 0.05% tumor DNA. Its performance in PDAC diagnosis and progression risk evaluation was evaluated using tissue (314 tumor vs. 306 normal) and plasma (187 PDAC vs. 59 normal) samples from two independent retrospective cohorts. A longitudinal cohort study (114 patients) was conducted to assess its performance in determining PDAC prognosis. Both before surgery and after surgery, plasma samples were collected. RESULTS:MIR129-2 methylation showed excellent performance in differentiating PDAC and normal tissues, with a sensitivity of 97.77% and a specificity of 98.71%. For the plasma samples, it had a high sensitivity of 87.20% and a specificity of 98.30%. Survival analysis revealed its ability to predict postoperative survival outcomes even in CA19-9-negative patients ( P = 0.001). CONCLUSION:Postoperative measurement of ctDNA-based MIR129-2 methylation can be used to predict PDAC recurrence risk, offering a cost-effective assay to facilitate the postoperative management of PDAC patients.