mRNA-Based Neoantigen Vaccines in Pancreatic Ductal Adenocarcinoma (PDAC)—A Promising Avenue in Cancer Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with 5-year survival rates consistently below 5% despite advances in surgery, chemotherapy, and targeted therapy. Worldwide, PDAC remains highly lethal, with 458,918 new cases and 432,242 deaths in 2018-about a 94% mortality-to-incidence ratio. The limited therapeutic efficacy is largely attributed to the pronounced heterogeneity of the disease, late clinical presentation, and the strongly immunosuppressive tumor microenvironment. In recent years, mRNA-based vaccines encoding patient-specific neoantigens have emerged as a promising immunotherapeutic modality. By delivering tailored antigenic sequences, these vaccines are capable of eliciting potent cytotoxic T-cell responses against tumor-restricted epitopes, thereby enhancing tumor immunogenicity while minimizing off-target effects. This review summarizes the biological rationale underlying mRNA vaccination in PDAC, recent progress in preclinical and early clinical trials, and key obstacles related to antigen selection, delivery platforms, and the immunosuppressive stroma. The potential integration of neoantigen mRNA vaccines into multimodal therapeutic strategies, including immune checkpoint inhibition and chemotherapy, is also discussed, underscoring their prospective role in overcoming resistance mechanisms and improving clinical outcomes in PDAC. However, most current data come from early-phase trials, with long-term benefits yet unproven. Definitive conclusions on efficacy and survival await results from ongoing randomized studies expected by 2028-2029. Further progress in neoantigen identification, delivery systems, and combination strategies is crucial to fully harness mRNA vaccine potential in PDAC.