METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy

Yasi Pan; Huarong Chen; Xiang Zhang; Weixin Liu; Yanqiang Ding; Dan Huang; Jianning Zhai; Wenchao Wei; Jun Wen; Danyu Chen; Yunfei Zhou; Cong Liang; Nathalie Wong; Kwan Man; Alvin Ho-Kwan Cheung; Chi Chun Wong; Jun Yu

doi:10.1016/j.xcrm.2023.101144

METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy

Cell Rep Med. 2023 Aug 15;4(8):101144. doi: 10.1016/j.xcrm.2023.101144.

Authors

Yasi Pan¹, Huarong Chen², Xiang Zhang¹, Weixin Liu¹, Yanqiang Ding¹, Dan Huang³, Jianning Zhai¹, Wenchao Wei¹, Jun Wen¹, Danyu Chen¹, Yunfei Zhou¹, Cong Liang¹, Nathalie Wong⁴, Kwan Man⁵, Alvin Ho-Kwan Cheung⁶, Chi Chun Wong¹, Jun Yu⁷

Affiliations

¹ Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
² Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China.
³ Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴ Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁵ Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
⁶ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁷ Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: junyu@cuhk.edu.hk.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy of NAFLD-HCC are still unclear. Here, we identify that the N⁶-methyladenosine (m⁶A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation, while Mettl3 knockout exerted the opposite effect in mice. Single-cell RNA sequencing revealed that METTL3 suppressed antitumor immune response by reducing granzyme B (GZMB⁺) and interferon gamma-positive (IFN-γ⁺) CD8⁺ T cell infiltration, thereby facilitating immune escape. Mechanistically, METTL3 mediates sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) mRNA m⁶A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters that impair CD8⁺ T cell function in the tumor microenvironment. Targeting METTL3 by single-guide RNA, nanoparticle small interfering RNA (siRNA), or pharmacological inhibitor (STM2457) in combination with anti-programmed cell death protein 1 (PD-1) synergized to reinvigorate cytotoxic CD8⁺ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Immunotherapy
Interferon-gamma / metabolism
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Methyltransferases* / genetics
Mice
Non-alcoholic Fatty Liver Disease* / complications
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / therapy
Tumor Microenvironment

Substances

Interferon-gamma
Methyltransferases
Mettl3 protein, mouse