Targeting Mettl8-Tcf1 axis promotes CD8+ TPEX differentiation and antitumor immunity
Year: 2026
Type: article
Abstract: CD8+ T cell exhaustion represents a major obstacle to effective cancer immunotherapy. While stem-like progenitor exhausted T (TPEX) cells can differentiate into intermediate (Int-TEX) and terminally exhausted (TEX) subsets, the epigenetic regulation of this process is unclear. We identify the RNA methyltransferase Mettl8 as a critical regulator, with expression significantly higher in TPEX than in TEX subsets. In anti-PD-1 responding non-small cell lung cancer patients, Mettl8 and the stemness factor TCF7 were downregulated. In murine models, Mettl8 deletion restrained tumor progression by driving TPEX differentiation into effective Int-TEX cells. Mechanistically, Mettl8 stabilizes Tcf7 mRNA via m3C modification and enhances Tcf1 protein expression. Additionally, Mettl8 interacts with Tcf1 to facilitate chromatin looping at the Tox locus, maintaining TPEX stemness. Pharmacological Mettl8 inhibition promoted TPEX-to-Int-TEX differentiation and tumor control. Combining this inhibition with anti-PD-1 therapy yielded synergistic efficacy. Our findings establish Mettl8 as a pivotal regulator of TPEX fate and a promising therapeutic target for enhancing immunotherapy.
DOI: 10.1084/jem.20250424
Authors: Jiaxi Song, Dan Cui, Jiabao Wang, Xuewei Qi, Jiaxin Ma, Qing Liu, Jing Yang, Haoyu Yu, Lilin Ye, Qizhao Huang, Jia Li, Fengyin Li
Institutions: University of Science and Technology of China, Guangzhou Laboratory, Changping Laboratory, Chongqing Medical University, First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou Medical University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7141762013