Lactic acid facilitates the generation of regulatory T cells and promotes cancer progression by activating latent TGF-β1.

Lactate accumulation and the acidic tumor microenvironment play pivotal roles in tumor immune evasion, and regulatory T cells (Tregs) constitute a major barrier to effective anti-tumor immunity. However, whether lactate or the acidic microenvironment can drive the generation of Tregs, and the underlying mechanisms involved, remain poorly understood. Here, we demonstrate that the expression of FOXP3 is positively correlated with the expression of LDHA across multiple tumor types. Lactic acid, but not sodium lactate, enhanced the expression of FOXP3 by activating the latent TGF-β1, which derived from the culture medium containing fetal bovine serum or produced by tumor cells. Knockdown of LDHA in tumor cells reduced the production of lactic acid and significantly delayed tumor growth in immunocompetent mice, accompanied by a decrease in Tregs and an enhancement of anti-tumor function of T cells. Our findings reveal a novel mechanism by which lactic acid facilitates the generation of Tregs and promotes cancer progression, and further suggest that targeting lactic acid metabolism or the acidic tumor microenvironment may represent a promising therapeutic strategy.