Lactate as a Metabolic Regulator in the Tumor Microenvironment: Linking Immunosuppression to Epigenetic Reprogramming

A defining characteristic of tumor cells is their preferential reliance on aerobic glycolysis for lactate production, even under oxygen-sufficient conditions - the well-known Warburg effect. Recent advances have revealed lactate to be far more than a metabolic waste product, establishing its role as a versatile signaling molecule with multiple functions in cancer progression. Acting simultaneously as a pro-inflammatory mediator, hypoxia surrogate, tumor burden indicator, and metastasis predictor, lactate exerts profound and wide-ranging effects on immune cell function within the tumor microenvironment (TME). The immunomodulatory properties of lactate create a profoundly immunosuppressive milieu that facilitates tumor immune evasion. It achieves this through coordinated suppression of antitumor immune effectors, including natural killer cells, dendritic cells, and cytotoxic T lymphocytes, while simultaneously enhancing the immunosuppressive functions of regulatory T cells, tumorassociated macrophages, and endothelial cells. This dual mechanism of action promotes tumor progression and metastasis through multiple pathways. The groundbreaking discovery of lysine lactylation (Kla) has further expanded our understanding of lactate's biological roles, revealing a direct molecular connection between tumor metabolism and epigenetic regulation. This review provides a comprehensive synthesis of current knowledge regarding lactate-mediated immune modulation in the TME, examines recent advances in our understanding of lactate-dependent tumor biology, and evaluates emerging therapeutic strategies that target lactate metabolism. By integrating these perspectives, we aim to offer both fundamental insights and practical guidance for the development of novel anticancer therapies that target metabolic-epigenetic crosstalk.