Targeting Mettl8-Tcf1 axis promotes CD8+ TPEX differentiation and antitumor immunity

  • J Exp Med. 2026 May 4;223(5):e20250424. doi: 10.1084/jem.20250424.
Jiaxi Song  #  1 ,  Dan Cui  #  2 ,  Jiabao Wang  1 ,  Xuewei Qi  1 ,  Jiaxin Ma  1 ,  Qing Liu  1 ,  Jing Yang  1 ,  Haoyu Yu  1 ,  Lilin Ye  3  4 ,  Qizhao Huang  5 ,  Jia Li  6  2  7 ,  Fengyin Li  1
Affiliations
  • 1. State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, China.
  • 2. Guangzhou National Laboratory , Guangzhou, China.
  • 3. Institute of Immunological Innovation and Translation, Chongqing Medical University , Chongqing, China.
  • 4. Changping Laboratory , Beijing, China.
  • 5. Department of Hepatobiliary Surgery, The First Affiliated Hospital, Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China.
  • 6. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Joint International Research Laboratory of Respiratory Health, Guangdong Basic Research Center of Excellence for Respiratory Medicine, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University , Guangzhou, China.
  • 7. China-Portugal Artificial Intelligence and Public Health Technologies Joint Laboratory, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangdong Provincial Key Laboratory of Respiratory Disease Research, Guangzhou Medical University , Guangzhou, China.
  • # Contributed equally.
PMID: 41891923 DOI: 10.1084/jem.20250424
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.

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