The Warburg effect, the observation that cancer cells preferentially metabolize glucose through glycolysis even in the presence of oxygen, has been a defining feature of cancer metabolism for nearly a century. This metabolic reprogramming results in substantial lactate production, which has traditionally been viewed as a waste product. However, emerging research has revealed that lactate serves functions beyond metabolic byproduct, acting as a signaling molecule and substrate for post-translational modifications.
Lactylation, the addition of a lactyl group to lysine residues on proteins, was first described in 2019 as a novel histone modification. This discovery established a direct link between cellular metabolism and epigenetic regulation, as lactate levels influence the extent of histone lactylation and consequently gene expression. Since this initial description, lactylation has been detected on numerous non-histone proteins, expanding its functional repertoire.
The enzymatic machinery responsible for lactylation is still being elucidated. Evidence suggests that both enzymatic and non-enzymatic mechanisms contribute to lactylation. The balance between lactylation and delactylation, mediated by putative eraser enzymes such as histone deacetylases, determines the functional consequences of this modification. Understanding this regulatory system is an active area of investigation.
In cancer, lactylation has been implicated in multiple aspects of tumor biology. Histone lactylation promotes expression of genes involved in cell proliferation, angiogenesis, and metastasis. The modification is enriched at promoters and enhancers of oncogenes and growth-promoting genes, linking high lactate levels in the tumor microenvironment to pro-tumorigenic gene expression programs.
Immune modulation represents another important function of lactylation in cancer. Tumor-derived lactate can induce lactylation in immune cells, altering their function and contributing to immune suppression. Macrophages exposed to high lactate show increased lactylation of genes associated with the M2 immunosuppressive phenotype. This mechanism may contribute to the immunosuppressive tumor microenvironment that limits the efficacy of immunotherapy.
Therapy resistance has also been linked to lactylation. Cancer cells that survive chemotherapy or radiation often show elevated lactate production and increased lactylation. The modification can promote expression of drug efflux pumps, DNA repair enzymes, and anti-apoptotic proteins, collectively conferring resistance. Targeting lactylation may therefore sensitize tumors to conventional therapies.
The prognostic significance of lactylation is increasingly being recognized. Elevated levels of lactylation markers correlate with poor outcomes in multiple cancer types, including glioblastoma, hepatocellular carcinoma, and breast cancer. These associations suggest that lactylation could serve as a biomarker for risk stratification and treatment selection.
Therapeutic targeting of lactylation is at an early stage but holds promise. Strategies include inhibition of lactate production through glycolysis inhibition, blockade of lactate transporters to reduce intracellular lactate levels, and development of specific inhibitors targeting the lactylation machinery. Combination approaches pairing lactylation inhibitors with chemotherapy, radiation, or immunotherapy could enhance treatment efficacy.
Several challenges remain in translating lactylation research into clinical applications. Specific and sensitive methods for detecting lactylation in clinical samples need to be developed and validated. The tissue and context specificity of lactylation effects require further characterization. The safety of targeting lactylation, given its roles in normal physiology, must be established.
Future research directions include identification of the full repertoire of lactylated proteins in cancer, elucidation of the enzymes responsible for adding and removing lactylation, and investigation of crosstalk between lactylation and other post-translational modifications. Clinical trials targeting lactate metabolism or lactylation could establish the therapeutic potential of this emerging target.
DOI:10.1007/s11684-026-1212-4