Histone lactylation: a new target for overcoming immune evasion and therapy resistance.

While metabolic reprogramming in cancer is well-documented, the epigenetic consequences of lactate accumulation-particularly histone lactylation-remain underexplored as a unifying mechanism driving immune evasion and therapy resistance. This review synthesizes emerging evidence that lactylation remodels the tumor microenvironment (TME) by polarizing macrophages, exhausting T cells, and stabilizing oncogenic transcripts. We highlight the dual roles of lactylation as both a metabolic sensor and a mediator of immunosuppression, underscoring its potential as a therapeutic target. Unresolved questions, such as context-dependent effects of specific lactylation sites (e.g., H3K18la and H3K9la) and the interplay with other post-translational modifications, are critically evaluated. We also propose strategies to exploit lactylation pathways for combination therapies.