[Research progress on protein lactylation modification in malignant tumors]

Malignant tumors, a class of diseases characterized by abnormal proliferation and aggressive growth, pose a severe threat to human health. A hallmark of tumor cell biology is the pervasive presence of the Warburg effect, wherein cells undergo high-rate glycolysis leading to substantial lactate production, even under aerobic conditions. Traditionally regarded merely as a metabolic waste product, lactate has been re-evaluated through recent research, which reveals it to be not only a crucial metabolite but also a significant signaling molecule. It exerts core regulatory functions in gene expression and cellular activity through a novel post-translational modification: Protein lactylation. The seminal discovery of histone lactylation unveiled a direct and novel mechanistic link between cellular metabolic states and epigenetic regulation. Subsequent proteomic studies have substantiated that lactylation is a widespread modification existing across various types of non-histone proteins, establishing it as an important regulatory mechanism. The process of lactylation modification is dynamic and reversible, orchestrated by specific "writer" enzymes that catalyze its addition and "eraser" enzymes that facilitate its removal. Within the context of malignant tumors, lactylation modification participates extensively in tumorigenesis and progression by targeting two primary classes of substrate proteins: Histones and non-histone proteins. At the epigenetic level, histone lactylation remodels chromatin state and reprograms gene expression profiles. At the functional level, lactylation of non-histone proteins directly modulates the activity of key signaling pathway components, metabolic enzymes, and DNA repair factors. The synergistic action of these two facets collectively drives core malignant phenotypes, including remodeling of the tumor immune microenvironment, facilitation of metastasis and dissemination, induction of therapy resistance, and dysregulation of metabolism. This review provides a systematic overview of the discovery, molecular mechanisms, and recent advances concerning the roles of lactylation in tumor metabolism, immunity, and treatment resistance. It further explores potential therapeutic strategies targeting lactylation, such as modulating lactate metabolism, intervening in the enzymatic machinery of the modification system, and developing specific blocking agents. Although challenges remain regarding the specificity of the involved enzymes and the functional validation of these modifications, in-depth research on lactylation offers a fresh perspective for understanding the crosstalk between tumor metabolism and epigenetics. It also lays a theoretical foundation for the development of innovative strategies for cancer diagnosis and therapy.