Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy

作者：Kaixin Wu, Sa Li, Guangliang Hong, Hongzhi Dong, Tongke Tang, Liu He, Lingmei Jin, Siyuan Lin, Jingyun Ji, Mingli Hu, S.C. Chen, Haoyuan Wu, Haoyuan Wu, Guan‐Zheng Luo, Haoyuan Wu, Haoyuan Wu, Xiangqian Kong, Jiekai Chen, Jiangping He, Hongling Wu, Hongling Wu · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.70089 · 被引用次数：22 · 研究领域：RNA modifications and cancer、Ubiquitin and proteasome pathways、T-cell and Retrovirus Studies

ABSTRACT Background Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6‐methyladenosine (m 6 A) is known to be involved in tumourigenesis. However, the role of m 6 A in regulating T‐cell function and enhancing anti‐tumour immunity remains unexplored. Methods Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m 6 A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA‐seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single‐cell RNA‐seq (scRNA‐seq). Furthermore, in vitro and in vivo T‐cell cytotoxicity killing assay and CRISPR Cas9‐mediated m 6 A reader YTHDF1‐3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m 6 A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells. Results We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T‐cell function, thereby enhancing responsiveness to ICB th...