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

purposeGastric 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.

methodsA 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.

resultsKnockdown 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.

conclusionThis 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.