CXCL11 recruits immunosuppressive cells to form a barrier at the invasive front of pancreatic cancer by activating the NF-κB/CCL2 axis

Background Pancreatic ductal adenocarcinoma is a malignancy characterized by profound immunosuppression and universal resistance to immunotherapy. The complex tumor microenvironment is a critical determinant of therapeutic failure. The chemokine C-X-C motif chemokine ligand 11 (CXCL11) exerts dual immunomodulatory roles in various tumors; however, its expression pattern, clinical significance, and molecular mechanisms in pancreatic cancer remain unclear. Methods This study integrated clinical cohort analysis, tissue microarray, transcriptomic sequencing, and in vitro functional experiments. Immunohistochemistry and multiplex immunofluorescence were used to analyze CXCL11 expression and its spatial relationship with immune cell infiltration. Transcriptomic sequencing was performed to identify differentially expressed genes after CXCL11 knockdown, followed by pathway enrichment analysis. CXCL11 knockdown and overexpression models were established in Panc02 and SW1990 cell lines, and western blotting was used to verify the regulatory effects on the nuclear factor kappa-B (NF-κB) signaling pathway and downstream C C motif chemokine ligand 2 (CCL2) expression. Results CXCL11 expression was higher in paratumor tissues than in tumor tissues of pancreatic cancer, and its high expression was significantly associated with shortened overall survival and more aggressive pathological features. Co-enrichement of CXCL11 with immunosuppressive markers such as CD163, CD11b, and programmed death-ligand 1 in paratumoral regions suggests its involvement in forming a spatially heterogeneous immunosuppressive barrier. Tissue-level analysis revealed a significant positive correlation between CXCL11 expression and the M2 macrophage marker CD163, as well as the myeloid-derived suppressor cell marker CD11b. Transcriptomic and functional experiments confirmed that CXCL11 activates the NF-κB signaling pathway and upregulates CCL2 expression. Tissue microarray further validated their positive correlations at the protein level. Conclusions CXCL11 plays a pro-tumorigenic role in pancreatic cancer, with high expression levels predicting poor prognosis. By activating the NF-κB signaling pathway to upregulate CCL2, CXCL11 drives the "CXCL11–NF-κB–CCL2″ signaling axis, which, together with its enrichment in paratumoral regions, promotes the recruitment and activation of immunosuppressive cells and forms a functional immunosuppressive barrier at the invasive front. This provides a mechanistic explanation for immunotherapeutic resistance in pancreatic cancer and suggests CXCL11 and its related pathways as potential therapeutic targets.