Lysine Lactylation: Dynamic Regulation in the Tumor Microenvironment and Clinical Translational Prospects

ABSTRACT

This review systematically explores the dynamic regulatory roles of lysine lactylation (Kla) in the tumor microenvironment (TME) and its clinical translational potential. As an emerging post‐translational modification, Kla modifies histones and non‐histone proteins via lactate generated by the Warburg effect, thereby reshaping tumor metabolism and immune landscapes. Mechanistically, Kla orchestrates metabolic reprogramming and immunosuppression through key signaling pathways such as HIF‐1α, mTOR, and NF‐κB. Specifically, it promotes the activation of immunosuppressive cells while inhibiting cytotoxic CD8 ⁺ T cells and NK cells, fostering tumor immune escape. Preclinical studies demonstrate that targeting lactate metabolism or lactylation enzymes restores immune effector functions and enhances immune checkpoint therapy efficacy. However, challenges such as tumor heterogeneity, metabolic plasticity, and systemic toxicity remain. Future research should focus on Kla's crosstalk with other epigenetic modifications, spatiotemporal dynamics in TIME, and clinical translation to unlock its potential as a biomarker and precision oncology target.