The lactylation axis: bridging metabolic reprogramming and immunosuppression in the tumor microenvironment

Protein lactylation, a novel post-translational modification (lysine lactylation, Kla) driven by the oncometabolite lactate, has emerged as a critical epigenetic mechanism that directly links cellular metabolic state to gene regulation. Within the tumor microenvironment (TME), lactate accumulation resulting from the Warburg effect provides abundant substrate for lactylation, positioning this modification as a central hub in cancer biology. This review systematically elucidates the dual role of lactylation in driving tumor progression. Intrinsically, lactylation promotes tumor cell malignancy by globally reshaping chromatin accessibility via histone modifications (e.g., H3K18la) and orchestrating oncogenic signaling pathways through non-histone protein modifications, thereby enhancing metabolic reprogramming, proliferation, invasion, and therapy resistance. Extrinsically, lactylation serves as a key immunosuppressive mechanism by reprogramming the function of immune cells within the TME. It drives macrophages toward an M2-like immunosuppressive phenotype, enhances the suppressive function of regulatory T cells (Tregs), and induces dysfunction and exhaustion in CD8+ T cells, collectively fostering an immune-privileged niche. We further discuss the promising therapeutic strategies targeting the lactylation axis, including inhibitors of lactate production or lactyltransferases, and their combination with immune checkpoint blockade, to reverse immunosuppression and overcome treatment resistance. In summary, understanding the lactylation axis establishes a novel metabolic-epigenetic-immune paradigm and suggests potential new frameworks for precision cancer therapy.