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

KRASG12D 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 KRASG12D inhibition and its synergy with natural killer (NK) cell therapies. We demonstrate that KRASG12D 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, KRASG12D 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 KRASG12D inhibitors with NK cell-based immunotherapies to improve outcomes for patients with KRASG12D-mutant cancers.