Interleukin-35 and pancreatic cancer: research progress from tumor-promoting mechanisms to treatment resistance

Interleukin-35 (IL-35) is an immunosuppressive cytokine whose expression levels are elevated in tumor tissues and serum of pancreatic cancer patients and are associated with disease prognosis. This article is a narrative review that summarizes the multiple tumor-promoting functions of IL-35 in pancreatic cancer and their underlying mechanisms. Current evidence suggests that IL-35 drives pancreatic cancer progression and treatment failure through the following mechanisms: (1) directly acting on tumor cells to enhance proliferation and inhibit apoptosis; (2) reshaping the immune microenvironment, including inducing Breg-mediated immunosuppression, promoting T-cell dysregulation, driving tumor metastasis and angiogenesis, and promoting liver fibrosis; (3) mediating resistance to chemotherapy and immunotherapy. All of the above mechanisms are supported by relevant literature. Building on this foundation, this review further proposes three potential mechanisms—involving immune positive-feedback amplification, bidirectional regulation of EMT, and neural microenvironment remodeling—based on the known functions of IL-35 in other pathological contexts. These mechanisms remain to be validated. Unlike previous pan-cancer reviews of IL-35, this review focuses specifically on the unique tumor microenvironment of pancreatic cancer. It integrates the fragmented evidence regarding IL-35 in pancreatic cancer, constructs a mechanistic framework of “tumor cell autonomy—microenvironment remodeling—treatment resistance,” and extrapolates some potential pathways that have not yet been explored, thereby providing a new theoretical perspective for a deeper understanding of the pathological mechanisms of pancreatic cancer and the exploration of IL-35-targeted therapeutic strategies.