Cancer cells often rely on an inefficient energy process known as the Warburg effect, where glucose is converted to lactate even in the presence of oxygen. This excess lactate is not merely waste—it fuels an epigenetic process called lactylation. In lactylation, lactate is transformed into lactyl-CoA and attached to lysine residues on histone and non-histone proteins by enzymes such as ACSS2 and GTPSCS. This modification alters gene expression, enabling tumor growth and resistance to therapy.
Lactylation enhances resistance to chemoradiotherapy by promoting DNA repair mechanisms like homologous recombination through modification of proteins such as NBS1 and MRE11. It also drives the overexpression of drug efflux transporters and supports cell survival via processes like epithelial–mesenchymal transition and autophagy. In immunotherapy resistance, lactylation shapes an immunosuppressive tumor microenvironment by converting macrophages from the anti-tumor M1 type to the pro-tumor M2 type, increasing regulatory T cells, and impairing cytotoxic T-cell function through PD-L1 upregulation. It further suppresses innate immunity by modifying proteins like cGAS.
Targeting lactylation offers new therapeutic potential. Strategies include blocking glycolytic enzymes or lactate transporters to reduce lactate production, or directly inhibiting the lactylation process with agents such as Givinostat or demethylzellal. Ultimately, lactylation serves as a crucial link between altered cancer metabolism and the genetic programs that sustain tumor survival and immune evasion.