Oncostatin M promotes immune escape, invasion, and metastasis of pancreatic cancer by upregulating PD-L1 via the PI3K/AKT pathway.

Pancreatic cancer is characterized by rapid progression and high mortality, while the overall benefit of immune checkpoint inhibitors remains limited, highlighting the need for more effective immunotherapeutic strategies. Through bioinformatic screening and clinical tissue analyses, we found that oncostatin M (OSM) expression is closely associated with both PD-L1 levels and tumor metastasis in pancreatic cancer, suggesting its potential as a novel immunotherapeutic target. Western blot (WB), qPCR, and flow cytometry demonstrated that OSM markedly upregulates PD-L1 expression at both the transcriptional and protein levels in pancreatic cancer cells. In a pancreatic cancer cell-PBMC co-culture model, CFSE proliferation assays, intracellular flow cytometry, ELISA, and LDH release assays showed that OSM significantly suppresses CD8 T-cell proliferation, activation, effector cytokine secretion, and cytotoxicity. Meanwhile, wound-healing and Transwell assays revealed enhanced migratory and invasive capacities of pancreatic cancer cells in the presence of OSM. Notably, PD-L1 neutralizing antibodies effectively reversed OSM-induced immunosuppression and tumor cell migration and invasion. Mechanistically, WB analysis indicated that OSM upregulates PD-L1 expression via activation of the PI3K/AKT axis, and the PI3K inhibitor LY294002 abrogated the OSM-driven immunosuppressive and promigratory phenotypes. In vivo imaging, immunofluorescence, and hematoxylin-eosin (HE) staining further confirmed that OSM promotes tumor growth and metastasis, elevates PD-L1 expression, reduces immune infiltration, and suppresses the production of key effector cytokines such as IFN-γ. Collectively, our findings demonstrate that OSM enhances PD-L1 expression through the PI3K/AKT pathway, thereby facilitating immune evasion and metastatic progression in pancreatic cancer, and reveal a potential therapeutic window for immunomodulatory intervention.