EVA1A facilitates glycolysis in esophageal squamous cell carcinoma to boost PLAU histone lactylation and dampen CD8 ⁺ T cell activity

Endogenous retrovirus group E member 1 (EVA1A) is expressed in various normal tissues and plays a role in tumor development. However, its function in esophageal squamous cell carcinoma (ESCC) and immune regulation remains unclear. Bioinformatics, clinical samples, and in vivo/in vitro experiments were used to evaluate EVA1A expression and function. A co-culture system with CD8+ T cells, as well as a xenograft mouse model, was established. CD8+ T cell activity, glycolysis markers, lactate levels, and PLAU expression were assessed through flow cytometry, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent (ELISA), lactate dehydrogenase (LDH) assays, and chromatin immunoprecipitation (ChIP). EVA1A was upregulated in ESCC and negatively correlated with CD8+ T cell infiltration. EVA1A knockdown suppressed tumor growth and immune escape by reducing glycolysis and lactate production. Lactate promoted histone H4K12la lactylation, enhancing plasminogen activator-urokinase (PLAU) expression. PLAU overexpression reversed CD8+ T cell activation induced by EVA1A silencing. High EVA1A expression enhances glycolysis in ESCC, and the resulting lactate further induces H4K12la lactylation and promotes PLAU expression. This inhibits the anti-tumor activity of CD8+ T cells, suggesting that EVA1A has potential as a therapeutic target for ESCC.