Lactylation Orchestrates Immune Evasion in Gastric Cancer through KDM5B-Mediated Histone Demethylation.
basic_science · Level V
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- Record sourced from PubMed, PMID 42489575.
- Also identified by DOI 10.1158/0008-5472.CAN-25-5071.
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Abstract
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. 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.