Metabolic-epigenetic rewiring in cancer: The role of lactylation in tumor progression, immune evasion, and therapy resistance.

Research shows that lysine lactylation (kla) represents a novel post-translational modification that links cancer metabolism with epigenetic regulation. The production of lactate through the Warburg effect is associated with the lactylation of both histone and non-histone proteins, which regulate key gene expression programs linked to tumor progression, therapy resistance, and immune evasion. This review integrates recent findings on how elevated glycolysis levels, along with increased lactate concentrations in the tumor microenvironment (TME), trigger transcriptional activation through lactylation-mediated mechanisms. It highlights how lactylation interacts with other acylations, contributes to the development of cancer stemness, remodels the immune landscape, and reduces drug efficacy across various tumor types. Elevated lactylation expression correlates with poor patient outcomes, diminished CD8⁺ T cell infiltration, and increased expression of immune checkpoint proteins at tumor sites, thereby creating an immunosuppressive environment. The survival of cancer cells depends in part on lactylation, as it enhances DNA repair efficiency, protects against ferroptosis, and regulates genes associated with therapeutic resistance. Researchers are currently evaluating novel therapeutics that target enzymes involved in lactate metabolism (LDH, MCTs) and epigenetic "writers" of lactylation, such as p300/ CREB-binding protein, to disrupt oncogenic signaling pathways. The diagnostic relevance of lactylation is also gaining attention, as it serves as a potential biomarker for tumor progression and treatment response. As a critical epigenetic regulatory mechanism, lactylation opens new avenues for the development of precise cancer therapies, warranting further in-depth investigation.