Lactate, once viewed as a metabolic by-product of glycolysis, is now recognized as a central regulator in cancer biology. Accumulating evidence reveals that lactate actively participates in tumor progression by functioning as a metabolic fuel, signaling mediator, epigenetic modifier, and immune modulator. Tumor cells exhibit elevated glycolytic flux through the Warburg effect, producing large quantities of lactate through LDHA and exporting it through MCTs, which acidifies the tumor microenvironment and drives metabolic symbiosis, angiogenesis, and immune evasion. Lactate also stabilizes HIF-1α and activates the receptor GPR81, triggering signaling pathways that promote proliferation, invasion, and immune checkpoint expression. Epigenetically, lactate regulates histone acetylation and lactylation, modulating gene expression and supporting adaptive transcriptional programs. Immune suppression is reinforced through direct inhibition of effector T and NK cells and expansion of Tregs and MDSCs. Given its multifaceted role, lactate metabolism has emerged as a promising therapeutic target. Inhibitors of LDHA, MCT1/4, and GPR81 are under active development and show synergistic potential with immunotherapy and chemoradiotherapy. This review summarizes current advances in lactate biology and therapeutic strategies, highlighting the need for personalized approaches that consider tumor-specific lactate dependencies and signaling contexts.
Tian et al. (2025) studied this question.