Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits response to immunotherapy. Tumor-infiltrating B cells (TIBs) constitute a key TME component, and in certain patient subsets, they collaborate with T cells, dendritic cells, and other immune cells to form tertiary lymphoid structures (TLSs). Current evidence reveals functionally distinct TIB subsets in PDAC; while some subsets promote tumor progression, others enhance anti-tumor immunity. Therefore, comprehensively elucidating these dualistic roles is imperative. Concurrently, the presence of mature TLSs within PDAC correlates with improved prognosis and therapeutic outcomes. Understanding TIB and TLS dynamics, along with their interactions with other TME components, may unveil novel strategies to overcome immune suppression in PDAC. This review synthesizes recent advances in TIB and TLS research, evaluates their prognostic significance, and explores potential clinical applications.

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is common and complex, accompanied with chemotherapy process. Gemcitabine-based chemotherapy regimens have shown limited antitumor effects for PDAC, and combination targets are urgently needed to restrict chemoresistance. We attempted to identify the candidate targets with gemcitabine (Gem) through scRNA-seq and bulk-seq analysis based on chemotherapy-treated and Gem-resistant (GR) samples, respectively. The mechanisms were investigated with experimental validation in vitro and in vivo preclinical PDAC models. We found that chemoresistance and evolution after chemotherapy of PDAC were associated with activation of focal adhesion signal. Mechanistically, the focal adhesion kinase (FAK) inhibitor (IN10018) could restrict chemoresistance to Gem of PDAC by targeting SLC7A11-mediated ferroptosis through PI3K-Akt signaling pathway. For tumor microenvironment, IN10018 reduced the abundance of mesenchymal components and enhanced CD8+ T cell infiltration.

Abstract Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is partly driven by pathological stromal remodeling, yet the underlying mechanisms remain poorly understood. Here, we show that gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts via the senescence-associated secretory phenotype, leading to progressive fibrotic matrix stiffening. This biomechanical reprogramming engages the mechanosensitive ion channel Piezo1, triggering metabolic rewiring that renders BRG1-positive tumor cells increasingly dependent on NRF2-mediated antioxidant defenses. Piezo1 signaling promotes NRF2 nuclear translocation and its chromatin-remodeling cooperation with BRG1, thereby upregulating SLC7A11-dependent antioxidant programs and suppressing ferroptosis. Notably, the combination of the senolytic agent ABT-263 with the ferroptosis inducer Erastin effectively dismantles BRG1–NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic–ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.

e16370 Background: The optimal treatment strategy for patients with synchronous pancreatic ductal adenocarcinoma with liver metastases (sPDACLM) remains uncertain, and the role of surgery in selected patients is controversial. Comparative evidence regarding survival outcomes between upfront surgery (US) and surgery following systemic therapy (SS) in this population is limited. This study aimed to compare overall survival (OS) among patients with sPDACLM treated with different therapeutic strategies and identify prognostic factors associated with survival. Methods: This multicenter retrospective cohort study included patients with sPDACLM treated at seven tertiary medical centers in China between 2017 and 2025. Patients were categorized into three groups: upfront surgery group (US), effective systemic therapy followed by surgery (E-SS), defined as achievement of partial response [PR] per RECIST 1.1 with a > 85% reduction or normalization of serum CA19-9 after systemic therapy; and ineffective systemic therapy followed by surgery (I-SS), defined as fails to achieve PR or < 85% reduction in CA19-9 after systemic therapy. The primary endpoint was OS. Results: A total of 72 patients were included, comprising 21 in the US group, 24 in the E-SS group, and 27 in the I-SS group. Baseline characteristics differed substantially among groups, with 21 of 24 covariates demonstrating a standardized mean difference (SMD) > 0.1. Kaplan–Meier analysis showed significantly improved survival in the E-SS group compared with the US group (median OS: 31.9 vs. 8.0 months; 1-year OS: 90.47% vs. 33.33%; 3-year OS: 40.50% vs. 15.23%) and the I-SS group (median OS: 17.0 months; 1-year OS: 66.62%; 3-year OS: 0%) (P < 0.0001). Univariate Cox regression identified effective systemic therapy as a favorable prognostic factor for OS (hazard ratio [HR], 0.265; 95% CI, 0.123–0.571; P < 0.001). After adjustment for clinically relevant covariates, multivariable Cox analysis confirmed that effective systemic therapy (adjusted HR [aHR] = 0.225, 95% CI: 0.099–0.512; P < 0.001) and tumors located in the pancreatic body–tail region (aHR = 0.443, 95% CI: 0.222–0.882; P = 0.03) were independently associated with prolonged OS. Sensitivity analyses yielded consistent results, supporting the robustness of the findings. Conclusions: Among patients with sPDACLM, treatment strategies incorporating systemic therapy are associated with improved survival compared with upfront surgery. Moreover, tumors arising in the pancreatic body–tail region represent an independent favorable prognostic factor. These findings support prioritizing systemic therapy in the management of sPDACLM, with subsequent surgical resection following systemic therapy offering a clinically meaningful survival benefit.

Although pancreatic ductal adenocarcinoma (PDAC) tumors harbor unique intracellular bacteria, therapeutic strategies to harness them and overcome immunotherapy resistance remain elusive. Through 16S rDNA sequencing of PDAC tumors from 40 patients and screening of probiotic strains, we identified Bifidobacterium longum (B. longum) as capable of colonizing tumors and invading PDAC cells. In a murine orthotopic tumor model, B. longum's anti-tumor effects are exclusively driven by rapamycin-induced xenophagy. This xenophagy-mediated probiotic therapy, termed XenoPro, significantly suppresses tumor growth by presenting B. longum-derived neoantigens and eliciting robust CD4+ T cell activation and tumor-specific cytotoxicity. From 40 predicted neoantigens, a vaccine containing the top 12 immunogenic neoantigens showed potent anti-tumor effects and prolonged survival in murine models of PDAC, colorectal cancer, and melanoma. XenoPro, administered orally or intravenously, enhances immune cell infiltration and improves the efficacy of immune checkpoint inhibitors, offering a promising strategy for PDAC immunotherapy.

Robotic surgery is a transformative approach for abdominal tumors. With the emergence of multiple robotic systems, evidence on their comparative oncological outcomes remains limited. This two-center prospective observational cohort study aimed to compare surgical efficacy and short-term oncological outcomes between the novel KangDuo Surgical Robot System-2000 (KD-SR-2000) and the Da Vinci Xi system in robot-assisted distal pancreatectomy (RDP). This two-center prospective observational cohort study enrolled patients with pancreatic tumors who scheduled for RDP at Peking Union Medical College Hospital and Peking University First Hospital between December 2023 and May 2025. Eligible patients were assigned into either the KD-SR-2000 group (n = 33) or the Da Vinci Xi group (n = 50) in a non-randomized, non-blinded manner. Baseline demographics, perioperative parameters, postoperative complications, ergonomics, and hospitalization costs were prospectively collected and compared between groups. Baseline characteristics were balanced. One case in the Da Vinci Xi group was converted to laparotomy due to severe adhesions and splenic vein bleeding. No significant differences were observed in surgical success, conversion, spleen preservation, or 90-day mortality rates (all P > 0.05). NASA-TLX scores indicated higher physical demand, effort, and total workload in the KD-SR-2000 group, though differences were not significant (all P > 0.05). Major complications (Clavien-Dindo ≥ III) and specific complications showed no significant differences. The KD-SR-2000 group had significantly lower hospitalization costs (8131.6 [7642.4–9960.7] vs.9859.6 [9022.4–18,965.8], P < 0.001). Intraoperative blood loss, operation time, and postoperative stay did not differ significantly. In this preliminary prospective observational study, the KD-SR-2000 system demonstrated comparable efficacy and safety to the Da Vinci Xi in the RDP procedure. While further improvements are needed in its ergonomic design, it possesses significant advantages in surgical costs and may be considered a viable alternative to the Da Vinci Xi system.

Liver metastasis is a major factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). The formation of pre-metastatic niche (PMN) initiates the process of liver metastasis. Exosomes (Exos) act as key mediators of crosstalk between the tumor microenvironment (TME) and the PMN to activate hepatic stellate cells (HSCs) and remodel the stiff extracellular matrix (ECM). In this study, we isolated Exos derived from PDAC cells cultured under acidic conditions and demonstrated that these Exos significantly activate HSCs and promote the remodeling of the stiff ECM, thereby promoting the stemness, migration, and invasion of PDAC cells. High expression of exosomal miR-1246 was screened by miRNA-sequencing, and Wiskott-Aldrich syndrome protein Family Member 3 (WASF3) was identified as the target of miR-1246. Mechanistically, exosomal miR-1246 activates HSCs to remodel the ECM by targeting WASF3 and stimulating the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K/Akt) pathway. Notably, RNA-binding protein immunoprecipitation (RIP) and miRNA pull-down assays were performed to identify that Human Antigen R (HuR) contributes to the enrichment of miR-1246 into Exos. Collectively, exosomal miR-1246 activates HSCs and remodels the stiff ECM to promote liver metastasis, and it may serve as a potential diagnostic and prognostic marker for PDAC liver metastasis.

Acute pancreatitis (AP) is an inflammatory disorder with no efficient therapy. Here we demonstrate that the anorexigenic peptide nesfatin-1 exerts potent and dose-dependent protection against both caerulein-induced and hypertriglyceridemic AP. Intraperitoneal administration of nesfatin-1 to restore its serum levels significantly reduced pancreatic necrosis, edema, and infiltration of immune cells, as well as circulating levels of amylase, lipase, and pro-inflammatory cytokines. RNA-seq revealed that nesfatin-1 down-regulated the ER-stress signature (Ddit3, Atf3, Ppp1r15a) and the NF-κB/NLRP3 signaling. Further studies in primary acinar cells confirmed that nesfatin-1 at the dose of 10 nM suppressed phosphorylated eIF2α, DDIT3, ATF3, p65, and NLRP3, thereby inhibiting pyroptosis. Consequently, nesfatin-1 attenuated macrophage/neutrophil infiltration, shifted M1 toward M2 macrophages, inhibited the release of inflammatory cytokines, and alleviated multi-organ injury in lung, intestine, and spleen. Collectively, nesfatin-1 limits AP severity by restraining ER-stress-driven pyroptosis and innate immune activation. Thus, nesfatin-1 may serve as a promising therapeutic candidate for acute pancreatitis.

With regard to laparoscopic approach, the objective arises whether standard multiorgan Whipple resection (PD) or parenchyma-sparing procedures (DPPHRt) are the most qualified surgical treatments for benign, premalignant neoplasms. Pubmed, Embase, Medline, and Cochrane Libraries were searched for studies reporting results and late outcomes after laparoscopic DPPHRt (L-DPPHRt) and laparoscopic PD (L-PD) for benign tumors. Data of 19 cohort studies including 459 patients were assessed. Results of six controlled trials comprising 129 L-DPPHRt and 205 L-PD for benign neoplasms were compared. L-DPPHRt was performed for 123 IPMNs, 44 MCNs, 98 SPNs, 102 SCNs, and 59 PNETs. 90-day mortality was 2 of 459 patients (0.43

BACKGROUND:Accumulating evidence has demonstrated that distinct tumour-promoting and tumour-restraining cancer-associated fibroblast (CAF) subtypes coexist in pancreatic ductal adenocarcinoma. OBJECTIVE:To develop targeted CAF therapeutic strategies by reprogramming tumour-promoting CAF subtypes. DESIGN:We leveraged multiomics technologies to systematically identify and characterise CAF subtypes transcriptionally, epigenetically and spatially and correlate them with clinicopathological features. RESULTS:We found that complement-secreting CAFs (csCAFs), initially identified by our group and inflammatory CAFs (iCAFs) share significant overlap in their transcriptional profiles and chromatin accessibility. iCAFs specifically express transcription factors from the heme and oxidative homeostasis pathway and the activator protein 1 family, which are both involved in cellular response to oxidative stress. Notably, the composition of csCAFs among all CAFs declined during pancreatic carcinogenesis, while trajectory analysis showed that csCAFs could potentially differentiate into iCAFs. Spatially resolved analysis indicated that tumour regions with a higher csCAF composition were associated with lower levels of TGF-β ligands, fewer M2 tumour-associated macrophages and increased levels of lipid mediators. Additionally, we identified a spatially defined CXCL12-CXCR4 ligand-receptor interaction between csCAFs and T cells, but in distinct patterns between different metastatic organs. Patients with a higher composition of csCAFs have significantly longer overall survival and recurrence-free survival through multiplex immunohistochemistry and bulk RNA-seq deconvolution. CONCLUSION:Our study demonstrates that csCAFs may represent an early-stage iCAF subtype and suggests a promising strategy for reprogramming iCAFs into csCAFs.

Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with profound metabolic rewiring and resistance to therapy. Sodium-glucose co-transporter 2 (SGLT2) regulates glucose uptake, but its role in PDAC remains unclear. Methods SGLT2 expression was analyzed in clinical samples and public datasets. PDAC cell lines were subjected to genetic knockdown or canagliflozin (CANA) treatment to assess proliferation, migration, apoptosis, and glucose metabolism. Mechanistic studies investigated AMPK-ULK1 signaling, autophagy dynamics, oxidative stress, and EGFR signaling. Xenograft models were used to assess in vivo efficacy. Results SGLT2 was upregulated in PDAC and associated with poor prognosis. SGLT2 inhibition suppressed proliferation and migration while promoting apoptosis. Mechanistically, CANA induced ATP deficiency and initiated autophagy, but concurrently impaired autophagosome-lysosome fusion. This dual effect led to autophagic flux blockade, resulting in excessive ROS accumulation, mitochondrial dysfunction, and apoptosis. Inhibition of AMPK reduced ROS levels, while ROS scavenging partially rescued mitochondrial damage and cell death. Notably, SGLT2 inhibition enhanced sensitivity to EGFR-targeted therapy, producing synergistic anti-tumor effects in vitro and in vivo. Conclusions SGLT2 maintains metabolic and autophagic homeostasis in PDAC. Its inhibition induces metabolic stress, autophagic flux blockade, and ROS-driven mitochondrial apoptosis. In addition, targeting SGLT2 sensitizes tumors to EGFR-targeted therapy, offering a novel combinatorial strategy.

BACKGROUND:Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. There is a pressing need to identify novel prognostic biomarkers and therapeutic targets, particularly among secreted proteins which play critical roles in tumor progression and the tumor microenvironment. METHODS:We conducted an integrated bioinformatic analysis of transcriptomic data from TCGA-LIHC and GEO datasets to identify dysregulated secretory proteins and construct a prognostic model. The top candidate, STC2, was selected for functional validation. Immune cell infiltration was analyzed using ESTIMATE and CIBERSORT algorithms. The functional role of STC2 was investigated through in vitro assays including siRNA knockdown, overexpression, cell proliferation, colony formation, and wound healing. Mechanisms of transcriptional regulation were assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS:We established a robust risk-scoring model based on a signature of secretory proteins, which identified STC2 as a key prognostic determinant. High STC2 expression was linked to an immunosuppressive tumor microenvironment characterized by enriched macrophage infiltration. Furthermore, STC2 expression was significantly upregulated in HCC tissues and strongly associated with advanced tumor stage, metastasis, and reduced patient survival. Mechanistically, we demonstrated that the transcription factor HIF-1α directly binds to the STC2 promoter and activates its transcription. Functional studies confirmed that STC2 drives HCC cell proliferation, clonogenicity, and migration. Transcriptomic profiling further indicated that STC2 is involved in activating the PI3K-Akt and HIF-1α signaling pathways. Moreover, STC2 is highly expressed in tumor regions and is associated with M2-type macrophage polarization in TME. CONCLUSION:Our study unveils STC2 as a pivotal hypoxia-induced oncogene in HCC, directly transcriptionally activated by HIF-1α. STC2 fosters tumor progression by enhancing malignant phenotypes and sculpting an immune-suppressive microenvironment, positioning it as a promising prognostic biomarker and an attractive therapeutic target for HCC.

The stratification of pancreatic ductal adenocarcinoma (PDAC) remains challenging due to the limitations of current staging systems and the ineffectiveness of the serum biomarker CA19-9 in a significant patient subgroup. We developed and validated a deep learning-based pathomic signature (PCPSDL) using routinely acquired haematoxylin and eosin (H&E)-stained whole-slide images from 252 patients at our institution and an external cohort of 183 patients from TCGA. PCPSDL robustly predicted overall and recurrence-free survival (C-indices: 0.64 and 0.61 internally, 0.62 and 0.61 externally). Crucially, it effectively stratified CA19-9-negative patients into high- and low-risk groups with significantly distinct outcomes (OS: HR = 9.26, P < 0.001; RFS: HR = 5.02, P < 0.001). Biological interpretation linked the high-risk score to an immunosuppressive microenvironment and a basal-like epithelial cell state. Our study establishes PCPSDL as a powerful, biologically interpretable, and clinically actionable prognostic biomarker that could guide personalized therapy for PDAC, particularly for patients lacking conventional serological markers.

Solid-pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor with low malignant potential, most commonly occurring in the pancreatic body or tail of young women. Atypical presentations, particularly in male patients and cases involving the pancreatic head, may pose diagnostic and therapeutic challenges. This report highlights surgical management considerations in a patient with inconclusive preoperative findings. We report the case of a 37-year-old man with a large lesion initially interpreted as a retroperitoneal mass closely associated with the pancreatic head. Preoperative imaging could not definitively establish the tumor origin. Following multidisciplinary team (MDT) evaluation, a diagnostic resection strategy was adopted. Robot-assisted laparoscopic exploration revealed that the tumor originated from the pancreatic head with an exophytic growth pattern. Local tumor excision combined with limited pancreatic resection was successfully performed while preserving the main pancreatic duct. Histopathological examination confirmed the diagnosis of SPN. The patient recovered uneventfully and remained clinically stable at follow-up. This case illustrates the clinical decision-making process and surgical strategy selection in an atypical presentation of SPN with preoperative diagnostic uncertainty. The report underscores the potential role of robot-assisted surgery in facilitating precise dissection and parenchyma preservation in complex anatomical settings.

e16403 Background: Patients with pancreatic ductal adenocarcinoma (PDAC) liver metastases have a poor prognosis, and the best treatment remains uncertain. While systemic chemotherapy is standard, the benefit of liver metastasis resection in oligometastatic patients lacks high-level evidence, with many studies affected by bias and mixed results. This study evaluates the effect of synchronous liver metastasis resection on overall survival, adjusted for confounders through multicentre, propensity score-matched analysis, and identifies independent prognostic factors. Methods: This retrospective multicenter study in seven Chinese centers enrolled patients with pancreatic cancer and liver metastases from January 2017 to July 2025. Patients were divided into complete liver lesion management and partial/untreated groups based on intervention extent. Propensity score matching used covariates like sex, tumor location, and metastasis burden, with oligometastasis defined as < 3 lesions without extrahepatic spread. The primary endpoint was overall survival. Kaplan- Meier and Cox regression analysis compared groups and identified prognostic factors. Results: After matching, 48 patients (24 in each group) formed a balanced cohort. No significant baseline differences were found. Median survival was 19 months in the complete management group and 25 months in the partial/untreated group, with no significant difference (HR = 1.07. 07, P = 0. 853). Univariate analysis showed preoperative neoadjuvant chemotherapy, higher BMI, and lower ALT levels were associated with better prognosis. Multivariate analysis confirmed preoperative neoadjuvant chemotherapy and higher BMI as independent favorable factors. Subgroup analysis indicated complete metastasis management did not improve survival among those responding to neoadjuvant chemotherapy. Conclusions: This study found that aggressive liver metastasis resection does not significantly prolong survival. Systemic therapy, especially neoadjuvant chemotherapy, and nutritional status (BMI) are stronger prognostic factors. The results suggest focus should be on systemic and health management rather than aggressive surgery, providing high- level evidence supporting' chemotherapy over surgery" in this setting.

Pancreatic adenosquamous carcinoma(PASC)is a rare exocrine malignancy of the pan-creas with an increasing incidence,histologically defined by the coexistence of adenocarcinoma and squa-mous carcinoma components.Current pathological diagnosis typically requires the squamous component to comprise at least 30％of the tumor.However,this threshold remains controversial given the unconfirmed independent prognostic value of the extent of squamous differentiation.Compared with pancreatic ductal adenocarcinoma(PDAC),PASC exhibits greater aggressiveness and heterogeneity,contributing to a poorer prognosis with a median survival of approximately 9 months.Despite its distinct biological beha-vior,specific preoperative diagnostic methods and targeted therapeutic strategies remain elusive.Diagnos-tically,while PASC lacks specific molecular markers,the ring-enhancement sign observed in the arterial phase of contrast-enhanced CT may aid distinction from PDAC.Owing to the lack of standardized thera-peutic strategies,treatment largely follows guidelines established for PDAC,offering limited survival benefits,though platinum-based chemotherapy and radiotherapy show potential efficacy.Notably,the rationale for immunotherapy lies in the high programmed death-ligand 1(PD-L1)expression in the squa-mous component and an immunosuppressive microenvironment characterized by specific checkpoint inter-actions,such as the TIGIT-CD155 axis.Furthermore,the cellular origin and evolutionary trajectory of PASC remain debated.While monoclonal origin is the prevailing theory,it remains unclear whether the squamous component arises from adenocarcinoma transdifferentiation or from pancreatic pluripotent stem cells.At the molecular level,PASC shares genomic and transcriptomic features with PDAC yet maintains a distinct identity.Concurrently,its tumor microenvironment(TME)displays unique landscapes,diffe-ring significantly from PDAC in immune and stromal components like T cells,macrophages,and fibro-blasts.Moreover,marked intratumoral heterogeneity is observed between the adenocarcinoma and squa-mous carcinoma regions within the same tumor.Future efforts should prioritize multi-omics and laser mi-crodissection technologies to establish a refined molecular classification system,alongside the integration of liquid biopsy and artificial intelligence(AI)-assisted radiomics for accurate preoperative diagnosis.This comprehensive strategy is essential to shift clinical practice from empirical treatment to personalized precision medicine,ultimately improving outcomes for this refractory disease.This article systematically reviews the epidemiology and clinicopathological features of PASC,and specifically explores the therapeu-tic potential of platinum-based chemotherapy,radiotherapy,and immunotherapy.Furthermore,special attention is given to recent advances in monoclonal origin patterns,unique genomic and transcriptomic alterations,and TME heterogeneity.

Locally advanced pancreatic cancer (LAPC) is associated with a poor prognosis and limited therapeutic options. This study aimed to evaluate the efficacy and safety of nab-paclitaxel plus S-1 (SnP) as a first-line treatment in patients with previously untreated LAPC. In this multicenter, single-arm phase 2 trial conducted across four centers in China, eligible patients received up to eight cycles of nab-paclitaxel combined with S-1, followed by investigator-selected continuation strategies in the absence of disease progression or intolerable toxicity. The primary endpoint was the 6-month progression-free survival (PFS). Between April 2019 and March 2023, 60 patients were enrolled, of whom 48.3% completed induction therapy and 18.3% subsequently underwent surgical resection, with 10 achieving R0/R1 status. The 6-month PFS rate was 71.0% (95% CI: 57.6%-80.9%), while the median PFS and overall survival (OS) were 11.1 months and 20.2 months, respectively. The 12-month OS rate reached 83.3%. The objective response rate was 26.7%, and the disease control rate was 90.0%. Grade ≥3 treatment-related adverse events occurred in 53.3% of patients, most commonly neutropenia and leukopenia, with no treatment-related deaths observed. These findings suggest that SnP demonstrates promising antitumor activity with manageable toxicity in LAPC and may facilitate conversion to surgical resectability in a subset of patients. This clinical study was registered at ClinicalTrials.gov (NCT03885219).

ABSTRACT Background Tumor‐derived exosomes (TDEs) can carry diverse genetic material that modulates pancreatic cancer (PC) proliferation and invasion. Despite this, the involvement of microRNAs (miRNAs) in TDE‐mediated tumor progression in PC remains inadequately explored. Methods Ultracentrifugation was used to isolate exosomes derived from AsPC‐1 and BxPC‐3 cells. Cell proliferation was assessed by cell counting kit‐8 (CCK‐8) and plate colony formation assays. Cell migration and invasion were evaluated using Transwell assays. Real‐time polymerase chain reaction (RT‐PCR) was performed to detect the expression levels of miR‐4644 and Sprouty RTK Signaling Antagonist 3 (SPRY3). A dual‐luciferase reporter assay was conducted to verify the binding site between miR‐4644 and SPRY3. Orthotopic PC xenografts were established to validate the effects of SPRY3 and miR‐4644. Finally, the relative expression levels of SPRY3 were validated using PC tissue and matched adjacent non‐tumor tissue samples. Results MiR‐4644 was enriched in TDEs, and the inhibition of miR‐4644 reduced the proliferation, migration, and invasion of PC cells. SPRY3 was identified as a direct target of miR‐4644, which bound to the 3′‐UTR of SPRY3 and suppressed its expression. The inhibitory effects of SPRY3 on PC cell proliferation, migration, and invasion were partially counteracted by miR‐4644. Importantly, clinical data analysis revealed that SPRY3 expression was significantly downregulated in PC tissues (p < 0.05). Mechanistically, miR‐4644 targeted SPRY3 and promoted PC cell proliferation, migration, and invasion through the Ras–Raf‐MAPK signaling pathway. Conclusions MiR‐4644 is upregulated in PC TDEs and promotes PC cell progression by suppressing SPRY3 expression; high expression of exosomal miR‐4644 correlates with poor patient prognosis.

Pancreatic ductal adenocarcinoma (PDAC) has long been regarded as a prototypical immune-cold tumor because of its dense desmoplastic stroma,limited cytotoxic lympho-cyte infiltration,and poor response to immunotherapy.However,this definition is increasingly insufficient. Recent advances in single-cell sequencing,T-cell receptor (TCR)and B-cell receptor (BCR) repertoire profiling,single-cell immune receptor sequencing,three-dimensional (3D)genome technologies,spatial transcriptomics,spatial proteomics,and artificial intelligence (AI)-assisted data integration suggest that immune failure in PDAC is not merely a consequence of reduced immune effector cell abundance (1,2). Rather,it reflects a collapse of immune surveillance across spatial,clonal,structural,and systemic dimensions. Decoding PDAC tumor microenvironment(TME) from a multidimensional immunological perspective may therefore create new opportunities for early detection,risk stratification,and more effective immunotherapy.