Lactylation Orchestrates Immune Evasion in Gastric Cancer through KDM5B-Mediated Histone Demethylation

Immune evasion driven by the tumor microenvironment is a major obstacle to effective immunotherapy in gastric cancer. To overcome this barrier, a detailed understanding of the mechanisms by which gastric cancer circumvents antitumor immunity is essential. In this study, we identified KDM5B as a pivotal epigenetic-metabolic orchestrator of immune evasion in gastric cancer. Clinically, KDM5B overexpression correlated with poor prognosis and diminished CD8+ T-cell infiltration. Mechanistically, KDM5B suppressed NLRP3-dependent pyroptosis via H3K4me3 demethylation and inhibited JAK1-STAT1/3-driven chemokine production. Crucially, a lactate-KDM5B feedforward loop facilitated immunosuppression, with KDM5B promoting lactate production and K868 lactylation enhancing KDM5B activity. Therapeutically, dual targeting of KDM5B and glycolysis overcame anti-PD-L1 resistance. Overall, these findings establish KDM5B as a central hub integrating epigenetic reprogramming, metabolic rewiring, and immunosuppression to drive progression and immune escape, positioning KDM5B as an actionable therapeutic target for reversing immunotherapy resistance in gastric cancer. SIGNIFICANCE: KDM5B regulates an epigenetic-metabolic axis of immune evasion in gastric cancer that can be targeted to overcome anti-PD-L1 resistance, providing an effective combination immunotherapeutic strategy.