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METTL3 Inhibition Restores PD-L1 Expression and CD8+ T-cell Cytotoxic Function in Immunotherapy-Treated Gastric
Ming Fang1,2,3, Yaling Li1,3,4, Peng Wang1,5
1Key Laboratory of Dunhuang Medicine and Transformation at Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou, China.
Cancer Immunology Research
|April 29, 2025
Summary
Methyltransferase-like 3 (METTL3) epigenetically regulates PD-L1 mRNA degradation in gastric cancer (GC). Inhibiting METTL3 enhances anti-PD-1 immunotherapy efficacy by modulating the tumor microenvironment and boosting T cell activity.
Area of Science:
- Immunology
- Epigenetics
- Gastroenterology
- Oncology
Background:
- Immunotherapy targeting PD-1/PD-L1 is crucial for gastric cancer (GC) treatment, but its efficacy is influenced by PD-L1 expression and the tumor microenvironment (TME).
- Methyltransferase-like 3 (METTL3) is implicated in GC progression, yet its role in regulating the GC TME remains largely unknown.
Purpose of the Study:
- To investigate the mechanism by which METTL3 regulates PD-L1 expression and its impact on the tumor microenvironment in gastric cancer.
- To explore the potential of targeting METTL3 to enhance the efficacy of anti-PD-1 immunotherapy in GC.
Main Methods:
- Investigated METTL3's role in regulating PD-L1 mRNA stability via m6A modification in human GC cells.
- Assessed the impact of METTL3 knockdown/inhibition on immune cell activity and migration.
- Analyzed the correlation between METTL3, YTHDF2, and PD-L1 expression in clinical GC tissues.
- Evaluated the combined effect of a METTL3 inhibitor (STM2457) and anti-PD-1 antibody in vivo, assessing tumor growth, PD-L1 levels, and CD8+ T cell infiltration.
Main Results:
- METTL3 was found to mediate m6A modification of PDL1 mRNA, leading to its degradation through an m6A/YTHDF2-dependent pathway in GC cells.
- METTL3 inhibition enhanced immune cell cytotoxic activity and migration.
- Clinical GC samples showed a negative correlation between PD-L1 and METTL3/YTHDF2 expression.
- Combination therapy (METTL3 inhibitor + anti-PD-1 mAb) significantly reduced tumor growth, increased PD-L1 expression, and promoted CD8+ T cell infiltration.
- Lower METTL3 expression in tumors correlated with better response to anti-PD-1 immunotherapy.
Conclusions:
- METTL3-mediated epigenetic regulation of PD-L1 mRNA stability is a key mechanism influencing anti-tumor immunity in GC.
- Inhibiting METTL3 reshapes the TME, enhancing anti-PD-1 immunotherapy efficacy.
- Targeting METTL3 represents a promising strategy to improve immunotherapy outcomes for GC patients.
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