DataVXAdvanced SciencePaper
journal article·2026-02Open access

METTL5 Enables Immune Evasion of Liver Cancer via Chemokine mRNA Translation Regulation

Shuang Li, Xiao Zhao, Tongtong Song, Qiaoyi Chen, Yanqing Wu, Yuting Zhang, Jingying Chen, Yifan Wu, Bin Li, Xinyue Zhang, Zihao Dai, Lixia Xu, Yubin Xie, Alfred Sze‐Lok Cheng, Jianping Guo, Ming Kuang, Shuibin Lin, Zhenwei Peng, Sui Peng, Xuezhen Zeng

Advanced Science· Volume 13· Issue 11
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Source abstract

Abstract

Abstract The liver microenvironment is essential to immune surveillance and liver cancer progression. Here, the aim is to identify the role of METTL5, the 18S rRNA m 6 A methyltransferase, in regulating the liver immune microenvironment to promote cancer progression. Liver‐specific Mettl5 knockout (cKO) in mice exhibits increased immune cell infiltration, especially CD3 + and CD4 + T cells. Loss of Mettl5 inhibits intrahepatic cholangiocarcinoma (ICC) progression. By scRNA‐seq analysis, it is found that ICC from both cKO mice and human METTL5 low expression group correlates with increased CD8 + T cells but decreased macrophages, which is associated with better survival. Adoptive transfer of macrophages significantly promotes ICC progression. scRNA‐seq and scTCR‐seq analysis show that cKO mice exhibit reduced immunosuppressive Ms4a7 + C1qa + tumor‐associated macrophages (TAMs) but increased intratumoral IFN‐γ + CD8 + T cell infiltration and expansion. Mechanistically, METTL5‐mediated 18S rRNA m 6 A modification downregulates the mRNA translation of CXCL16 to exclude CD8 + T cells. Knockout of Mettl5 significantly increases CD8 + T cell infiltration in vivo. Combined METTL5 targeting using lipid nanoparticle‐encapsulated siRNA and PD‐1 blockade provokes anti‐tumor immunity to eradicate ICC tumors. Additionally, METTL5 Low human ICC correlates with responsiveness to immunotherapy. The study highlights the strong immuno‐evasive ability of METTL5 as a promising therapeutic target in ICC.
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Research context

Nanomaterials

OpenAlex topics: RNA modifications and cancer · Cancer-related molecular mechanisms research · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Liver Surgery Center of Hepato‐Pancreato‐Biliary Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Department of Radiation Oncology Cancer Center The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 510080 China

Department of Oncology The First Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 510080 China

Department of Gastroenterology and Hepatology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Department of Pathology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Clinical Trials Unit The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Institute of Precision Medicine the First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

School of Biomedical Sciences The Chinese University of Hong Kong Hong Kong 999077 China

Center for Translational Medicine The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities

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