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The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of cancer immunotherapy. Tumor metabolic reprogramming, particularly aerobic glycolysis (the Warburg effect), drives lactate accumulation in the TIME. Beyond fueling tumor growth, lactate-derived lysine lactylation (Kla) has emerged as a pivotal epigenetic and post-translational modifier, directly coupling metabolic activity to the regulation of immune cell function and tumor cell resilience.

This review synthesizes current evidence to delineate how the glycolysis-lactylation axis orchestrates a multi-faceted immunosuppressive program and confers broad therapy resistance. We detail its mechanisms in: (1) Inhibiting antitumor immunity by driving M2 macrophage polarization, enhancing regulatory T cell (Treg) function, and promoting CD8⁺ T cell exhaustion; (2) Enhancing intrinsic tumor cell resistance through lactylation-mediated DNA damage repair and stemness maintenance; and (3) Directly undermining immunotherapy, notably by stabilizing programmed cell death 1 ligand 1 (PD-L1). We critically evaluate emerging therapeutic strategies that target this axis, including inhibitors of glycolytic enzymes, lactate transporters (MCTs), and lactylation writers/erasers, and their potential to synergize with established immunotherapies.

Targeting the lactate-lactylation signaling hub represents a promising metabolic-epigenetic strategy to dismantle tumor-driven immunosuppression and overcome therapeutic resistance, particularly resistance to immunotherapy. Although a substantial body of preclinical evidence, ranging from cancer cell line models to patient-derived xenografts, supporting the potential of targeting this axis, its clinical translation remains hindered by a gap in the evidence hierarchy, necessitating further validation through prospective clinical trials.