KRAS^G12/13 mutation modulates CRC outcomes via disrupting positive feedback between macrophage and CD4⁺ T cell.

ABSTRACT: Kirsten rat sarcoma viral oncogene (KRAS) mutation influences colorectal cancer (CRC) progression, but their specific impact on the tumor immune microenvironment remains poorly defined. This study establishes that KRAS^G12/13 mutation disrupts critical positive feedback between macrophages and CD4⁺ T cells. Mechanistically, KRAS^G12/13-mutant tumor cells secrete elevated interleukin-10 (IL-10), which suppresses macrophage production of chemokine ligand 9/10 (CXCL9/10) and major histocompatibility complex II (MHC-II). This impairs the infiltration and activation of CXCR3⁺CD4⁺ T cells, fostering an immunosuppressive niche. By integrating multi-omics data from clinical cohorts and validating findings in vivo, we show that combining KRAS inhibitors with CXCL9/10 restoration effectively overcomes this immune suppression and controls tumor growth. Our work delineates a targetable immune evasion mechanism and provides a cohesive prognostic and therapeutic framework for KRAS^G12/13-mutant CRC.

SUBMITTER: Yan X 

PROVIDER: S-EPMC12809752 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature