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 H.K. Cheung, Chi Chun Wong, Jun Yu
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 N 6 -methyladenosine (m 6 A) 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 m 6 A 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.