Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications

Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.