2. Academic Validation
  3. METTL3 Inhibition Restores PD-L1 Expression and CD8+ T-cell Cytotoxic Function in Immunotherapy-Treated Gastric Cancer

METTL3 Inhibition Restores PD-L1 Expression and CD8+ T-cell Cytotoxic Function in Immunotherapy-Treated Gastric Cancer

  • Cancer Immunol Res. 2025 Jul 2;13(7):1037-1052. doi: 10.1158/2326-6066.CIR-24-1179.
Ming Fang # 1 2 3,  Yaling Li # 1 3 4,  Peng Wang # 1 5,  Yanan Wang 1 2,  Xiaoqian Wang 1 2,  Xiaoxia Wa 1 2 3,  Yu Zhang 1 2,  Zhenyu He 1 2,  Jiawei Li 1 2 3,  Ling Li 1 2 3,  Yun Su 1 2 3,  Huinian Zhou 6,  Jianzheng He 1 2 3,  Yongqi Liu 1 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Dunhuang Medicine and Transformation at Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou, China.
  • 2 Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China.
  • 3 College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China.
  • 4 NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China.
  • 5 School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China.
  • 6 The General Surgery Department, Lanzhou University Second Hospital, Lanzhou, China.
  • # Contributed equally.
PMID: 40299705 DOI: 10.1158/2326-6066.CIR-24-1179
Abstract

The efficacy of immunotherapy targeting PD-1/PD-L1 in gastric Cancer depends on PD-L1 expression levels and the infiltration of immune cells within the tumor microenvironment (TME). Although methyltransferase-like 3 (METTL3) plays a role in the development and progression of gastric Cancer, its mechanism of regulating the TME in gastric Cancer remains unclear. In this study, we demonstrated that the expression of PD-L1 is regulated by METTL3. We found that METTL3 mediated N6-methyladenosine (m6A) modification of PDL1 mRNA in the 3' untranslated region and induced mRNA degradation through an m6A/YTHDF2-dependent pathway in human gastric Cancer cells. METTL3 knockdown or inhibition in gastric Cancer cells significantly enhanced Jurkat cell migration and cytotoxic activity. In clinical gastric Cancer tissue, a negative correlation was observed between the expression levels of PD-L1 and those of METTL3 or YTHDF2. In vivo, combination treatment with the METTL3 Inhibitor STM2457 and PD-1 mAb resulted in a significant reduction in tumor growth, enhanced PD-L1 expression, and increased infiltration of CD8+ T cells. Finally, lower METTL3 expression in tumors correlated with improved sensitivity to anti-PD-1 immunotherapy in patients. Our findings revealed that METTL3-mediated m6A modification of PDL1 mRNA levels represents an epigenetic mechanism regulating antitumor immunity in gastric Cancer, and inhibiting METTL3 during PD-1 mAb treatment reshaped the TME, thereby establishing a promising treatment approach for enhancing immunotherapy efficacy in patients with gastric Cancer.

Figures
Products