KRAS mutations as architects of the tumor immune microenvironment: implications for combination therapies

Abstract

Oncogenic KRAS mutations rank among the most prevalent driver alterations in human malignancies, reaching near-universal frequency (~98%) in pancreatic ductal adenocarcinoma (PDAC) and high prevalence in colorectal cancer (CRC, ~52%) and lung adenocarcinoma (LAC, ~32%). Beyond their canonical roles in promoting cell-intrinsic proliferation and survival through the MAPK/ERK and PI3K/AKT cascades, KRAS mutations actively sculpt a profoundly immunosuppressive tumor microenvironment (TME), which constitutes a major barrier to both targeted therapy and immunotherapy. Through coordinated programs encompassing inflammatory cytokine secretion, downregulation of antigen presentation machinery, tumor-associated macrophage (TAM) reprogramming, myeloid-derived suppressor cell (MDSC) expansion, and PD-L1 upregulation, KRAS-mutant tumors establish robust immune exclusion. These programs are further stratified by co-mutations in STK11, KEAP1, and TP53, which define distinct immune phenotypes ranging from inflamed to profoundly immune-excluded “cold” tumors. The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines. This mini-review synthesizes the current knowledge of KRAS-immune crosstalk, highlights existing controversies and research gaps, and evaluates emerging combination strategies designed to convert immune exclusion into durable anti-tumor immunity.