Overcoming multidimensional immunotherapy resistance in PDAC: from microenvironment to clinic

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with immunotherapy yielding <10% objective response rates (ORR) due to its profoundly immunosuppressive tumor microenvironment (TME). This review integrates preclinical and clinical evidence (2018-2026) to dissect how stromal desmoplasia, myeloid dominance, T-cell exclusion, and impaired antigen presentation converge to form an immune-privileged niche. Key resistance pathways, including cGAS-STING, Hedgehog, and NF-κB, are discussed alongside emerging strategies such as CAR-T cells, mRNA neoantigen vaccines, STING agonists, CD39/CD73 blockade, and cDC1-based vaccines. Despite incremental progress, durable responses remain rare, emphasizing that single-target interventions are insufficient. We propose a "3D+R" framework, De-desmoplasia, De-adenosine, De-novo antigen, and Rational sequencing, to guide multidimensional, biomarker-driven immunotherapy design. Approaches such as timed cDC1 vaccination, patient-tuned STING agonism, and metabolic checkpoint inhibition exemplify how PDAC's immune-desert phenotype may be reshaped toward an immune-reactive state. Conceptualizing PDAC as a dynamic immune ecosystem rather than a mutation-driven entity may ultimately transform sporadic responses into durable and predictable clinical benefit.