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

Wenqi Du1,2, Lina Ding1, Jing Zhu1

  • 1Department of Pathology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China.

Cancer Research
|July 23, 2026
PubMed

Insights

KDM5B drives immune evasion in gastric cancer by altering epigenetics and metabolism. Targeting KDM5B and glycolysis can overcome immunotherapy resistance, offering a new treatment strategy.

Area of Science:

  • Oncology
  • Immunology
  • Epigenetics
  • Metabolism

Background:

  • Immune evasion in gastric cancer hinders effective immunotherapy.
  • Understanding gastric cancer's immune evasion mechanisms is crucial for therapeutic development.

Purpose of the Study:

  • To identify key regulators of immune evasion in gastric cancer.
  • To explore KDM5B's role in the epigenetic-metabolic axis of immune evasion.
  • To evaluate KDM5B as a therapeutic target for overcoming immunotherapy resistance.

Main Methods:

  • Clinical correlation analysis of KDM5B expression with patient prognosis and CD8+ T-cell infiltration.
  • Mechanistic studies on KDM5B's regulation of pyroptosis and chemokine production.
  • Investigation of the lactate-KDM5B feedforward loop.
  • In vivo and in vitro experiments assessing combination therapy targeting KDM5B and glycolysis.

Main Results:

  • KDM5B overexpression is linked to poor prognosis and reduced CD8+ T-cell infiltration in gastric cancer.
  • KDM5B suppresses NLRP3-dependent pyroptosis and inhibits JAK-STAT signaling-driven chemokine production.
  • A lactate-KDM5B feedforward loop promotes immunosuppression.
  • Dual inhibition of KDM5B and glycolysis overcomes anti-PD-L1 resistance.

Conclusions:

  • KDM5B acts as a central epigenetic-metabolic regulator of immune evasion and progression in gastric cancer.
  • Targeting KDM5B offers a promising strategy to reverse immunotherapy resistance in gastric cancer.
  • Combination therapy with KDM5B inhibition and glycolysis targeting presents a novel immunotherapeutic approach.

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