KRAS^G12D inhibition reprograms the tumor-induced immunosuppressive environment and enhances NK cell-mediated antitumor immunity.

Abstract

KRAS^G12D mutation drives oncogenic progression and creates an immunosuppressive microenvironment in cancers like pancreatic ductal adenocarcinoma and colorectal cancer. We investigate the immunomodulatory mechanisms of the KRAS^G12D inhibition and its synergy with natural killer (NK) cell therapies. We demonstrate that KRAS^G12D inhibition with MRTX1133 remodels the immune landscape by reducing myeloid-derived suppressor cell (MDSC) accumulation and facilitating infiltration and activation of NK and CD8⁺ T cells. Crucially, MRTX1133 reverses systemic immunosuppression, restoring the fitness of adoptively transferred NK cells. Mechanistically, KRAS^G12D inhibition impairs IFNGR1 palmitoylation and subsequent lysosomal degradation. MRTX1133 stabilizes IFNGR1 by reducing palmitoyltransferase expression and the palmitate pool. This stabilization increases IFN-γ/IFNGR signaling and up-regulates NK cell-activating ligands ICAM1 and ULBP1, thereby sensitizing cancer cells to NK cells. Consequently, combining MRTX1133 with IL-15 or adoptive NK cell therapy yields synergistic antitumor responses and prolonged survival. Our findings provide mechanistic rationale for combining KRAS^G12D inhibitors with NK cell-based immunotherapies to improve outcomes for patients with KRAS^G12D-mutant cancers.