Lactate metabolic reprogramming and lactylation modification: molecular mechanisms reshaping the tumor immunosuppressive microenvironment

The immunosuppressive tumor microenvironment (TME) remains a major therapeutic challenge in oncology. This immunosuppression arises through two synergistic mechanisms: impaired cytotoxic function of T cells and NK cells, and differentiation of immune cells into immunosuppressive subtypes. Metabolic reprogramming, particularly the Warburg effect (aerobic glycolysis in tumor cells), plays a pivotal role in shaping this immunosuppressive TME. While lactate was traditionally viewed as a metabolic byproduct, emerging evidence reveals its profound immunomodulatory functions. As the end-product of glycolysis, lactate actively reshapes immune cell behavior to foster immunosuppression. This review systematically examines: (1) the bidirectional lactate-mediated crosstalk between tumor and immune cells that drives immunosuppression, and (2) current therapeutic strategies targeting lactate metabolism. By elucidating these mechanisms, we aim to advance lactate-targeting approaches for TME reprogramming and improved cancer immunotherapy outcomes.