Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.

Lactate and its mediated modification, lactylation, are receiving increasing attention in the field of tumor biology. This review provides a comprehensive overview of the mechanistic involvement of lactate and lactylation in key oncogenic processes, such as tumor initiation, proliferation, invasion, metastasis, recurrence, and drug resistance. Rather than being a passive byproduct of glycolysis, lactate actively shapes the tumor microenvironment (TME), modulates immune responses, drives metabolic adaptation, and influences epigenetic and transcriptomic regulation. Lactylation, as a novel epigenetic mechanism, links cellular metabolism with gene expression by modifying histone and nonhistone proteins, thereby regulating chromatin accessibility, immune evasion, and DNA repair. Notably, this article proposes a new perspective: lactate accumulation in certain tumors may constitute an adaptive metabolic strategy rather than a passive consequence of altered metabolism. This paradigm challenges the traditional perception of lactate as a metabolic waste, instead proposing its dual function as both a signaling molecule and a strategic modulator of tumor progression. The interplay of lactate-mediated signaling pathways, such as the PI3K/AKT, Hippo, Wnt, MAPK, and JAK/STAT pathways, further underscores the role of lactate in cancer progression. This review also explores therapeutic opportunities targeting lactate metabolism and lactylation, including inhibitors of LDH, MCTs, and lactylation-modifying enzymes, as well as the synergistic potential of combining lactate-targeted approaches with chemotherapy, immunotherapy, and targeted therapy. Overall, this review provides an integrative overview of lactate-mediated mechanisms and highlights their potential as targets for metabolism-oriented therapeutic interventions in oncology.