Role of CircRNA_0005075 in gastric cancer immune evasion through regulation of lactate metabolic reprogramming and histone lactylation.

PURPOSE: Gastric cancer remains one of the most lethal malignancies worldwide. While immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have significantly advanced the treatment of advanced gastric cancer, their efficacy exhibits marked heterogeneity among patients, with a substantial proportion showing primary insensitivity or rapidly developing resistance. Tumor metabolic reprogramming and the epigenetic regulation it mediates are recognized as important intrinsic mechanisms limiting the efficacy of immunotherapy; however, the underlying molecular regulatory network requires further elucidation. This study aimed to investigate the role and molecular mechanisms of circRNA_0005075 in gastric cancer immune evasion, specifically analyzing whether it influences the transcriptional expression of the immune checkpoint molecule PD-L1 by regulating lactate metabolic reprogramming and histone lactylation, and further shapes the therapeutic response to PD-1 monoclonal antibodies. METHODS: A co-culture system employing gastric cancer cell lines and T cells was used, combined with circRNA_0005075 knockdown and overexpression strategies, to assess its impact on T cell cytotoxic activity. Targeted metabolomics and lactate content measurement were employed to analyze metabolic alterations in tumor cells. Histone lactylation and their regulatory role at the PD-L1 promoter region were evaluated using ChIP-qPCR, and dual-luciferase reporter assays. In vivo, a mouse tumor model was established and treated in combination with PD-1 monoclonal antibody therapy to systematically evaluate the effect of circRNA_0005075 on immunotherapy efficacy. RESULTS: Knockdown of circRNA_0005075 significantly enhanced the ability of T cells to kill gastric cancer cells, accompanied by upregulation of GZMB and perforin expression. Metabolic analysis revealed that downregulation of circRNA_0005075 reduced lactate levels. Mechanistic studies demonstrated that the enrichment of H3K9la at the PD-L1 promoter region was closely associated with its transcriptional activity, and that circRNA_0005075 could regulate PD-L1 expression through the lactate metabolism-lactylation axis. In the in vivo model, knockdown of circRNA_0005075 significantly enhanced the anti-tumor efficacy of PD-1 monoclonal antibody, as evidenced by suppressed tumor growth and upregulation of immune effector molecules. CONCLUSION: This study reveals the molecular mechanism by which circRNA_0005075 promotes PD-L1 transcriptional expression and mediates gastric cancer immune evasion through the regulation of lactate metabolic reprogramming and the induction of histone lactylation. This finding provides a novel metabolomic-epigenetic explanation for understanding the heterogeneity in gastric cancer immunotherapy efficacy and suggests that circRNA_0005075 and its associated lactylation state hold research value as potential therapeutic targets or predictive biomarkers for treatment response.