KDM4B enhances immune surveillance via demethylating cGAS.

Cyclic GMP-AMP synthase (cGAS) serves as a crucial sentinel in innate immunity by sensing cytosolic DNA, yet the molecular mechanisms governing its activation remain incompletely understood. Here, we identify lysine demethylase 4B (KDM4B) as the specific demethylase that erases cGAS K350 methylation, facilitating its chromatin release and subsequent activation. Genetic ablation of Kdm4b compromised both antiviral immunity against HSV-1 infection and antitumor responses, while also diminishing the efficacy of anti-PD-1 immunotherapy. Mechanistically, KDM4B-mediated cGAS demethylation proved crucial for its proper subcellular distribution and activation. In the context of autoimmune diseases, we found that targeting KDM4B-cGAS axis through either genetic approaches or pharmacological inhibition of KDM4B with JIB-04 effectively ameliorated disease manifestations in both Trex1-deficient mice and peripheral blood mononuclear cells from Aicardi-Goutieres syndrome (AGS) patients. Collectively, this study demonstrated that KDM4B functions as a specific demethylase for cGAS, controlling its chromatin dissociation and subsequent activation, thereby providing a therapeutic rationale for targeting cGAS methylation in human diseases.