KRAS-Driven Immune Exclusion in Pancreatic Ductal Adenocarcinoma: Mechanisms and Therapeutic Reversal

Pancreatic ductal adenocarcinoma (PDAC) remains largely resistant to immunotherapy, with response rates below 5%. Emerging evidence suggests that immune exclusion in PDAC is actively maintained by oncogenic KRAS signaling. Mechanistic studies implicate three coordinated processes: autophagy-mediated degradation of MHC-I and impaired antigen presentation, expansion of suppressive myeloid populations, and desmoplastic stromal remodeling that restricts cytotoxic T-cell access to malignant epithelium. These barriers are at least partially reversible. Inhibition of autophagy restores surface MHC-I expression and re-enables antigen-dependent CD8+ T-cell killing. Suppression of KRAS pathway signaling remodels the myeloid compartment, alters stromal architecture, and increases intratumoral CD8+ T-cell infiltration in experimental systems. Recent studies further demonstrate that combining allele-specific KRAS inhibition with multi-arm immunotherapy can produce durable responses in resistant PDAC models. Spatial profiling data also suggest that immune architecture differs by KRAS allele, with KRAS G12D tumors more frequently exhibiting stromal T-cell segregation and KRAS G12R tumors demonstrating altered immune proximity and metabolic dependence. Together, these findings support a model in which KRAS-targeted therapy functions not only as tumoricidal therapy but also as immune conditioning of the tumor microenvironment. Translating this biologic reversibility into durable clinical benefit will require rational, barrier-specific, and allele-informed combination strategies.