METTL14 Enhances Anti-Tumor Immunity through m6A-dependent loss of PD-1

  • Cancer Res. 2025 Aug 27. doi: 10.1158/0008-5472.CAN-25-0065.
Chang Huang  1 ,  Xiaodong Wang  2 ,  Yinmin Gu  3 ,  Ke Ren  4 ,  Haojing Zang  5 ,  Yibi Zhang  6 ,  Yongbo Pan  4 ,  Shuwen Cheng  7 ,  Xiaofeng Zhu  8 ,  Songzhe Wu  9 ,  Liqiang Duan  10 ,  Xiaojun Xu  11 ,  Qinong Ye  12 ,  Jian Zeng  13 ,  Hongbo Hu  14 ,  Shan Gao  15
Affiliations
  • 1. Guizhou University, Zunyi, China.
  • 2. , China.
  • 3. Chinese Academy of Sciences, suzhou, China.
  • 4. Zhongda Hospital Southeast University, China.
  • 5. Shanxi Medical University, taiyuan, China.
  • 6. CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engi-neering and Technology, Chinese Academy of Sciences, China.
  • 7. Nanjing University, China.
  • 8. Guizhou University, Gui Yang, China.
  • 9. Zhongda Hospital Southeast University, Nanjing, China.
  • 10. Shanxi Academy of Medical Sciences, China.
  • 11. Zhejiang University, China.
  • 12. Beijing Institute of Biotechnology, Beijing, China.
  • 13. Zhejiang Cancer Hospital, China.
  • 14. Sichuan University, Chengdu, Sichuan, China.
  • 15. Zhongda Hospital Southeast University, nanjing, China.
PMID: 40865050 DOI: 10.1158/0008-5472.CAN-25-0065
Abstract

N6-methyladenosine (m6A) modifications can impact immune responses by regulating different target genes. Here, we demonstrated that the programmed cell death-1 (PD-1) gene PDCD1 undergoes m6A modification, which subsequently impacts T cell function. METTL14 mediated PDCD1 downregulation in T cells by promoting m6A-dependent destabilization of PDCD1 mRNA, a process mediated by YTHDF1/2/3. Heterozygous METTL14 deficiency impaired the activation of CD8+ T cells and increased tumor growth by elevating PD-1 levels. Clinically, METTL14 was negatively associated with PDCD1 levels across various Cancer types and with resistance to PD-1-targeted immunotherapy. Moreover, WD6305, which degrades the METTL3-METTL14 complex, cooperated with anti-PD-1 therapy to suppress tumor growth in mice. Collectively, these findings reveal an immunoregulatory axis involving m6A modification of PDCD1 and highlight potential therapeutic strategies to enhance the efficacy of tumor immunotherapy.

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