2. Academic Validation
  3. Wild-type KRAS activation drives evasion of interferon-mediated immunity and resistance to immunotherapy in hepatocellular carcinoma

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

  • Nat Commun. 2025 Nov 11;16(1):9913. doi: 10.1038/s41467-025-64860-7.
Martina Mang Leng Lei 1,  Carmen Oi Ning Leung 1,  Rainbow Wing Hei Leung 1,  Xue Qian Wu 1,  Katherine Po Sin Chung 1,  Catherine Yu Jia Gu 1,  Mandy Sze Man Chan 1,  Wing Ki Chau 1,  Quan Hua Mu 1,  Kai Yu Ng 2,  Man Tong 3,  Jing Ping Yun 4,  Jia Ming Nickolas Teo 2,  Guang Sheng Ling 2 5,  Patrick Pak Chun Wong 3,  Stephen Lam Chan 6,  Zhe Wen Xiong 3,  Alfred Sze Lok Cheng 3,  Jin Ding 7,  Stephanie Ma 2 8,  Terence Kin Wah Lee 9 10
Affiliations

Affiliations

  • 1 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
  • 2 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 3 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 4 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 5 Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 6 Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
  • 7 Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, China.
  • 8 State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
  • 9 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China. [email protected].
  • 10 Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China. [email protected].
PMID: 41219194 DOI: 10.1038/s41467-025-64860-7
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-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.

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