Histone lactylation drives METTL3 upregulation-mediated RNA m6A modification of CCT2 to hinder CD8+ T cell survival in gastric cancer

Histone lactylation represents a novel epigenetic modification that can modulate gene expression, further boosting tumor proliferation, metastasis, and immune suppression. However, whether histone lactylation affects immune evasion in gastric cancer (GC) remains to be elucidated. WB and IHC were employed to assess the levels of H3K18la in tumor tissues. CCK-8, colony formation, T cell killing, ELISA, cytotoxicity experiments, and T cell chemotaxis experiments were undertaken to determine the biological functions of histone lactylation and METTL3. RNA-seq, WB, and CHIP experiments were utilized to validate the regulatory role of H3K18 lactylation in METTL3 transcriptional activity. The RIP assay was undertaken to verify the post-transcriptional modification of METTL3 protein on CCT2. The IF and flow cytometry were completed to analyze the regulatory mechanism of CCT2 on CD8 + T cells’ activity. IHC and IF were performed to detect protein expression in the homograft mouse model. Histone H3K18 lactylation was elevated in GC, promoting tumor proliferation, inhibiting cytotoxicity, and chemotaxis of CD8⁺T cells. Mechanistically, H3K18 lactylation boosted tumor immune suppression and in vivo tumorigenesis by upregulating METTL3 expression, while METTL3 enhanced CCT2 translation through m6A modification. CCT2 weakened CD8⁺T cell activity by inhibiting Ca²⁺ influx. METTL3 knockdown inhibited the immune escape of GC cells, while overexpression of CCT2 reversed the anti-tumor effect of METTL3 knockdown on CD8⁺T cells. Histone lactylation drives upregulation of METTL3 and mediates m6A modification and overexpression of CCT2. CCT2 dampens the activity of CD8 + T cells by repressing Ca 2+ influx, thereby mediating the malignant progression of GC.