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

作者：Martina Mang Leng Lei, Carmen Oi Ning Leung, Rainbow Wing Hei Leung, Xiaomeng Wu, Katherine Po Sin Chung, Chundong Gu, Mandy Sze Man Chan, Wing Ki Chau, Qingxin Mu, Kai‐Yu Ng, Man Tong, Jing‐Ping Yun, Jia Ming Nickolas Teo, Guang Sheng Ling, Patrick Y. Wong, Stephen L. Chan, Zhe Wen Xiong, Alfred S.L. Cheng, Jin Ding, Stephanie Ma, Terence K. Lee · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64860-7 · 被引用次数：4 · 研究领域：Cancer Immunotherapy and Biomarkers、interferon and immune responses、Single-cell and spatial transcriptomics

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-lucOSOE/Tp53KO 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. Increasing evidence suggests that activation of oncogenic pathways contributes to an unfavorable tumor microenvironment. Here, the authors show that wild-type KRAS plays a key ro...