The growing landscape of lysine lactylation links to immunosuppressive microenvironment.

Lysine lactylation (Kla) has emerged as an epigenetic-metabolic regulatory mechanism linking post-translational modification (PTM) to immunosuppressive TME formation. Evidence supports its complex role in TME by modulating immune state transitions and augmenting tumor malignancy. However, the existence of specialized lactyltransferases and multiple crosstalk mechanisms remain debated. This review summarizes upstream and downstream regulatory factors influencing lactylation modification, comparing differential substrate modification patterns that diverge in their requirements for Lactyl-CoA biosynthesis, which contributes to gene expression or protein function. Furthermore, we explore the mechanism that the lactate-Kla axis drives tumor progression by orchestrating metabolic reprogramming, fostering therapy resistance, and suppressing T-cell cytotoxicity. Finally, we summarize the burgeoning field of anti-lactylation pharmacology, evaluating prospective therapeutic strategies from preclinical and clinical studies.