Immuno-Oncology in Pancreatic Ductal Adenocarcinoma: Biological Rationale, Clinical Progress, and Future Directions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, characterised by rising incidence, poor long-term survival, and profound resistance to systemic therapy. Its poor prognosis reflects late diagnosis, early metastatic spread, and a uniquely desmoplastic, immunosuppressive tumour microenvironment that limits both drug delivery and effective antitumour immunity. Although cytotoxic chemotherapy remains the therapeutic backbone, its clinical benefit is modest. In parallel, molecular profiling has revealed a limited but expanding set of actionable vulnerabilities; however, immuno-oncology has not yet replicated in PDAC the transformative impact observed in other tumour types. This review examines the evolving immuno-oncology landscape in PDAC, focusing on four principal domains: immune checkpoint blockade in MSI-H/dMMR disease, tumour microenvironment-directed therapies, adoptive cellular therapies, and therapeutic cancer vaccines. Taken together, available evidence suggests that progress in PDAC immuno-oncology will depend on biomarker-guided patient selection, earlier disease settings, minimal residual disease-directed approaches, and rational combinations that address immune exclusion, stromal and myeloid barriers, impaired T-cell priming, and adaptive resistance. While durable clinical benefit remains limited and most strategies remain in early-phase evaluation, emerging data from molecularly selected cohorts, adoptive cellular therapies, and personalised or shared-antigen vaccines provide a compelling rationale for continued refinement of immune-based approaches in PDAC.