Wild-type KRAS activation drives evasion of interferon-mediated immunity and resistance to immunotherapy in hepatocellular carcinoma

Abstract

Increasing evidence indicates that activation of oncogenic pathways contributes to an unfavourable tumour immune microenvironment (TIME), ultimately resulting in resistance to immunotherapy. Here, we aim to identify a critical oncogenic pathway involved in an antigen-expressing c-MYC-lucOS^OE/Tp53^KO hepatocellular carcinoma (HCC) mouse model that simulates immune response against tumour-associated antigens. Using data-independent acquisition proteomics, we reveal the role of wild-type KRAS in immune escaped mouse HCC tumours, with EGF concurrently activating EGFR/MEK/ERK signalling. Single cell RNA sequencing data analysis reveals that KRAS signalling intrinsically inhibits interferon-mediated MHC-I expression and extrinsically impairs CD8⁺ T cell activity due to the suppression of CXCL9 through the EGFR/MEK/ERK pathway. We observe KRAS activation in HCC patients who received immune checkpoint inhibitor (ICI) treatments, where it correlates with poor clinical outcomes. Notably, combination therapy with SOS1 inhibitor MRTX0902, Trametinib, and anti-PD-1 antibody effectively increased intratumoural CD8⁺ T cell infiltration and improved survival. Our study thus reveals that targeting wild-type KRAS signalling in combination with ICIs may serve as an effective treatment strategy for advanced HCC patients.