Significance: Metabolic end products and intermediates can exert signaling functions as chemical sources for histone posttranslational modifications, which remodel chromatin and affect gene expression. Among them, lactic acid is responsible for histone lactylation, a recently discovered histone mark that occurs in high lactate conditions, such as those resulting from the Warburg effect in cancer cells. Recent Advances: Late-breaking studies have advanced the knowledge on the mechanisms involved in histone lactylation, requiring independent nonenzyme and enzyme-dependent reactions, which is emerging as an important hallmark of cancer cells linking metabolic changes to gene expression reprogramming. Critical Issues: In this study, we give an overview about this new epigenetic modification, focusing on its mechanism of action in tumors and tumor microenvironment. Future Directions: Further investigation on the competition mechanism between lactylation and acetylation, as well as on the mechanisms by which lactate fluctuation can control a specific gene set in a given tissue, is needed in the coming years to exploit new anticancer therapeutic approaches. Antioxid. Redox Signal. 40, 236-249.
