Hypoxia Induces Immunosuppression by Silencing STING in Cancer.

Stimulator of IFN genes (STING), a key component of the cyclic GMP-AMP synthase/STING pathway, is crucial for nucleic acid sensing and plays a significant role in tumor immune responses. However, STING is often silenced in various cancers, aiding tumor development. This study showed that tumor hypoxia downregulates STING in multiple cancer types, suppressing downstream pathways and inhibiting immunogenic cell death. Hypoxia-induced downregulation of STING occurred in a HIF1α-dependent manner, and STING silencing was associated with epigenetic modifications mediated by lysine demethylases KDM1A and KDM5A, further exacerbated by oncometabolite dysregulation. In vivo, hypoxia affected the efficacy of STING agonists on tumor growth and immune responses. Inhibiting KDM1A reversed hypoxia-induced STING downregulation and reactivated STING in previously suppressed cancer cells. This study highlights the interaction between hypoxia, oncometabolites, and immune signaling in cancer and suggests that targeting KDM1A could restore the STING pathway and improve the efficacy of cancer therapy. SIGNIFICANCE: Hypoxia silences STING expression in a HIF1α-dependent manner that is mediated by KDM1A/KDM5A and oncometabolites, which can be reversed by targeting KDM1A as a potential strategy for enhancing cancer therapy responses.