The lactylation-immunosuppression network in cancer: driving a metabolic-epigenetic axis

The accumulation of lactate in the tumor microenvironment (TME), driven by the Warburg effect, is closely associated with immunosuppression. Lactate can contribute to this process through lysine lactylation, a novel post-translational modification. We propose a conceptual framework, the "Lactylation-immunosuppression network," that links tumor metabolic reprogramming to immune cell signaling and gene expression. This network highlights a metabolic-epigenetic axis linking lactylation to immunosuppression via a synergistic dual mechanism: long-term epigenetic programming via histone lactylation establishes a stable immunosuppressive transcriptome, while rapid, dynamic non-histone lactylation directly modulates protein activity and stability, thereby potentiating function. This review summarizes how lactylation may undermine anti-tumor immunity by remodeling myeloid and T cell compartments, fortifying immune checkpoint barriers, and creating self-reinforcing metabolic feedback loops. By elucidating this mechanism, we highlight novel therapeutic targets, propose a "kinetic threshold" model to resolve the paradoxical role of lactate, and provide a unified conceptual framework for developing next-generation immunotherapies and guiding future mechanistic studies.