Application prospects of tumor vaccines for pancreatic cancer: From TAAs to TSAs and combination strategies

Pancreatic cancer, a highly aggressive malignancy of the digestive system, exhibits therapeutic resistance due to its immunosuppressive tumor microenvironment (TME) and early metastatic potential. Cancer vaccines targeting tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) have emerged as promising immunotherapeutic strategies. TAA-based vaccines demonstrate T cell activation and tumor suppression in preclinical models, yet face limitations from antigen heterogeneity and immunosuppressive TME. TSA-directed vaccines, exemplified by personalized mRNA vaccines incorporating whole-exome sequencing-selected neoantigens, achieved long-term recurrence-free survival in 50% of vaccinated patients during phase I/II trials, with phase III data supporting synergistic efficacy when combined with chemotherapy and programmed death receptor 1 (PD-1) inhibitors. KRAS-targeted vaccines address common mutations (e.g., G12D, G12V) to broaden applicability. This review presents an updated summary of current tumor vaccine types, mechanisms, and clinical implications, while analyzing how combination therapies remodel TME infiltration and reverse T cell exhaustion to significantly improve survival outcomes. The discussion also addresses existing challenges and proposes future directions in pancreatic cancer vaccine development.