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

Martina Mang Leng Lei, Carmen Oi Ning Leung, Rainbow Wing Hei Leung, Xue Qian Wu, Katherine Po Sin Chung, Catherine Yu Jia Gu, Mandy Sze Man Chan, Wing Ki Chau, Quan Hua Mu, Kai Yu Ng, Man Tong, Jing Ping Yun, Jia Ming Nickolas Teo, Guang Sheng Ling, Patrick Pak Chun Wong, Stephen Lam Chan, Zhe Wen Xiong, Alfred Sze Lok Cheng, Jin Ding, Stephanie Ma and Terence Kin Wah Lee ()
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Martina Mang Leng Lei: The Hong Kong Polytechnic University
Carmen Oi Ning Leung: The Hong Kong Polytechnic University
Rainbow Wing Hei Leung: The Hong Kong Polytechnic University
Xue Qian Wu: The Hong Kong Polytechnic University
Katherine Po Sin Chung: The Hong Kong Polytechnic University
Catherine Yu Jia Gu: The Hong Kong Polytechnic University
Mandy Sze Man Chan: The Hong Kong Polytechnic University
Wing Ki Chau: The Hong Kong Polytechnic University
Quan Hua Mu: The Hong Kong Polytechnic University
Kai Yu Ng: The University of Hong Kong
Man Tong: The Chinese University of Hong Kong
Jing Ping Yun: Sun Yat-Sen University Cancer Center
Jia Ming Nickolas Teo: The University of Hong Kong
Guang Sheng Ling: The University of Hong Kong
Patrick Pak Chun Wong: The Chinese University of Hong Kong
Stephen Lam Chan: The Chinese University of Hong Kong
Zhe Wen Xiong: The Chinese University of Hong Kong
Alfred Sze Lok Cheng: The Chinese University of Hong Kong
Jin Ding: Naval Medical University
Stephanie Ma: The University of Hong Kong
Terence Kin Wah Lee: The Hong Kong Polytechnic University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64860-7

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