Effects of lactylation on the hallmarks of cancer (Review).

Lactylation, an emerging metabolism-dependent post-translational modification, serves as a core mechanism linking metabolic reprogramming with epigenetic regulation in establishing the multifaceted hallmarks of cancer. The present review systematically elucidates how lactylation dynamically regulates the functions of both histone and non-histone proteins, driving the acquisition of classical cancer hallmarks including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, activation of invasion and metastasis and replicative immortality. Furthermore, lactylation is intricately involved in enabling the emerging hallmarks of cancer, such as the maintenance of genome instability, shaping of a pro-inflammatory tumor microenvironment (TME), immune escape, metabolic reprogramming, unlocking phenotypic plasticity and non-mutational epigenetic reprogramming. By reshaping the interaction networks among cancer, stromal and immune cells within the TME, lactylation promotes the formation of an immunosuppressive microenvironment and enhances resistance to therapy. Targeting lactylation regulatory pathways (such as lactate dehydrogenase A inhibitors, monocarboxylate transporter inhibitors and delactylase activators) can reverse key hallmark phenotypes, highlighting novel therapeutic avenues for the development of precision anticancer strategies based on interrupting metabolic-epigenetic crosstalk.