Targeting IL-12 for pancreatic cancer immunotherapy: advances in delivery strategies and clinical translation.

Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to conventional immunotherapies due to its immunosuppressive tumor microenvironment. Interleukin-12 (IL-12), a potent immunostimulatory cytokine, has demonstrated remarkable therapeutic potential across a range of malignancies. However, systemic administration of IL-12 has been linked to severe dose-limiting toxicities, including cytokine release syndrome and multi-organ dysfunction, representing a persistent barrier to clinical translation. This review examines the rationale for IL-12-based immunotherapy in PDAC, synthesizing the current knowledge on immunotherapy approaches for this disease, IL-12's mechanisms of action in cancer treatment, and synergistic combination strategies. We describe three major delivery platforms that have emerged to overcome the limitations of systemic delivery due to toxicity: cellular encapsulation systems, virotherapy-mediated approaches, lipid nanocapsule formulations, polymer-based platforms, local electroporation-mediated transfection, and CAR-T combined therapy. These innovative strategies enable localized, sustained IL-12 expression within the tumor microenvironment while minimizing systemic exposure and associated toxicities. By safely harnessing IL-12's potent immunostimulatory properties, these next-generation delivery systems offer promising therapeutic avenues for PDAC and other immunotherapy-resistant malignancies.