Abstract

Immune evasion in colon cancer (CC) is largely driven by the functional suppression of NK cells, yet the specific regulatory role of ETV4 in this process remains poorly defined. We first analyzed ETV4 expression levels in CC through bioinformatics prediction and qPCR validation. A tumor-NK cell co-culture system was established to assess NK cell cytotoxicity and glycolytic metabolic profiles, which were examined via Seahorse and lactate/glucose assays. A nude mouse xenograft model combined with the glycolysis inhibitor 2-DG was applied for validation. ETV4 was significantly upregulated in CC tissues, and its high expression correlated with adverse clinical prognosis and decreased intratumoral NK cell infiltration. ETV4 potentiated tumor glycolysis by upregulating the expression of key glycolytic enzymes LDHA and PDK1, which consequently impairs NK cell cytotoxicity and the production of NK cell effector molecules. Glycolysis inhibition reversed this NK-cell suppression. ChIP-qPCR and dual-luciferase reporter assays validated that ETV4 transcriptionally activated LDHA. In vivo, ETV4 accelerated tumor growth via glycolysis, and this effect was blocked by 2-DG treatment. In conclusion, by transcriptionally activating LDHA, ETV4 facilitates glycolysis and thereby inhibits NK cell-mediated antitumor immunity in CC The ETV4-glycolysis axis may serve as a therapeutic target.