Lactate and lactylation: molecular insights into histone and non-histone lactylation in tumor progression, tumor immune microenvironment, and therapeutic strategies
Shuying Xiao, Suhang Zhang, Kai Sun, Qibo Huang, Qilin Li, Chuanyu Hu
Abstract
Investigating cancer metabolism is of paramount importance for understanding tumor biology and developing novel therapeutic strategies. Lactylation, a posttranslational modification facilitated by the glycolytic product lactate, plays a crucial role in regulating oncogenic signalling pathways. This review provides a comprehensive analysis of lactate metabolism, including its biosynthesis, compartmentalized transport, enzymatic network and structural features of lactate dehydrogenases, transporters, lactyltransferases and deacetylases. These enzymes contribute to malignant tumor progression through metabolic reprogramming and modulation of the immune microenvironment. Importantly, we emphasize that integrating cancer subtype-specific lactylation profiles with core signatures reveals promising therapeutic opportunities for targeting lactate shuttles, histone, and nonhistone lactylation mechanisms, and transcriptional networks regulated by lactylation. In the present review, we highlight the significant potential of targeting glycolysis and lactylation modifications in tumors to improve the efficacy of cancer treatments.