From mechanism to targeted therapy: Advances in histone lactylation‑driven cancer progression (Review)

As a novel lactate-derived post-translational modification, histone lactylation links metabolic reprogramming and epigenetic regulation in cancer.Histone lactylation, particularly at histone H3 lysine 18 lactylation (H3K18la), has been implicated in tumor initiation, progression, metastasis, immune evasion and therapy resistance.It modulates oncogenic pathways (such as PI3K/Akt/mTOR, NF-B, JAK/STAT) and metabolic pathways (such as glycolysis enhancement, fatty acid synthesis via stearoyl-CoA desaturase and glutamine metabolism) and by altering chromatin structure and gene transcription.In the tumor microenvironment, lactate-induced H3K18la polarizes macrophages toward an M2 phenotype, upregulates immune checkpoints and induces CD8 + T cells dysfunction, which promotes immunosuppression.However, CD8 + T cell-intrinsic lactylation may enhance antitumor immunity during checkpoint blockade.Histone lactylation also induces chemoresistance via autophagy activation, DNA repair and ferroptosis suppression.Therapeutic strategies targeting lactylation include inhibiting lactate transporters, glycolysis or regulation enzymes (such as E1A-binding protein, lysine acetyltransferase 2A and brahma-related gene 1).Furthermore, the clinical potential is emerging, with H3K18la and H4K5la serving as prognostic biomarkers in multiple types of cancer.However, key questions regarding the non-enzymatic modification mechanisms, identification of histone lactation regulatory enzymes and pan-cancer functional heterogeneity are yet to be elucidated.Future research should prioritize translational validation of lactylation-targeted therapies and their integration with existing regimens to overcome resistance and improve immunotherapy efficacy. Contents1. Introduction 2. Lactate metabolism and lactate transport 3. Histone lactylation in tumor progression 4. Histone lactylation modulates tumor progression by remodeling the tumor microenvironment (TME) 5. Histone lactylation and chemoresistance 6. Histone lactylation and immune checkpoint inhibitors 7. Current research status and future directions of histone lactylation in cancer diagnosis or treatment 8. Conclusions and research perspectives