Lactate and lactylation in cancer: mechanistic insights and therapeutic implications

Metabolic reprogramming is a central hallmark of cancer and involves extensive alterations in nutrient utilization, glycolytic flux, and metabolite homeostasis. Among these metabolic changes, enhanced lactate production and accumulation within the tumor microenvironment have emerged as important regulators of tumor biology. Lactate was previously regarded as a metabolic waste product. However, increasing evidence indicates that lactate functions as a bioactive metabolite through distinct mechanisms, including extracellular acidification, lactate-mediated signaling, and regulation of lysine lactylation. Lysine lactylation is a recently identified metabolite-derived post-translational modification that provides a potential molecular link between cellular metabolism and transcriptional regulation. In this review, we summarize the metabolic pathways controlling lactate generation, transport, and availability, and discuss current advances in the formation, regulation, and functional consequences of lactylation. We examine both histone and non-histone lactylation events and critically evaluate their potential roles in tumor proliferation, metabolic adaptation, stemness, immune microenvironment remodeling, and therapeutic resistance. Importantly, we distinguish lactate-associated phenotypes from mechanisms directly demonstrated to be lactylation-dependent and highlight current challenges in establishing causal relationships between lactylation events and cancer progression. We further discuss the translational potential of lactylation as a biomarker for malignant progression, prognosis, therapeutic stratification, and treatment resistance. Emerging strategies targeting lactate metabolism and lactylation-associated vulnerabilities are also reviewed, with particular emphasis on issues of molecular specificity, biomarker-guided patient selection, and the current absence of clinically validated lactylation-directed therapies. Overall, lactylation represents an emerging metabolic-epigenetic regulatory mechanism that connects cancer metabolism with functional adaptation. Further elucidation of this axis may provide new opportunities for identifying metabolic vulnerabilities and developing precision therapeutic strategies in cancer. Clinical Trial Number : N.A.