Abstract

The Cyclic GMP-AMP Synthase (cGAS) pathway is a central DNA-sensing axis that instructs type I interferon (IFN) programs and bridges innate and adaptive immunity. While direct STING agonists have dominated clinical translation, small-molecule cGAS modulators, both inhibitors and activators, are rapidly maturing. Inhibitors such as RU.521 and next-generation human-specific scaffolds provide tools for restraining auto-inflammation, whereas pharmacologic sensitization of cGAS can potentiate tumorintrinsic IFN and improve responses to chemotherapy or immunotherapy. Here we synthesize recent advances in medicinal chemistry and disease biology, highlight species selectivity and dosing-window pitfalls and propose practical biomarker sets to guide development. We outline indications where cGAS activation may be advantageous (host-directed antivirals, immunogenic tumors) versus contraindicated (IFN-driven autoimmunity) and we sketch a near-term research agenda to de-risk translation.

Keywords:cGAS; STING; Small-molecule; Host-directed antivirals; Cancer immunotherapy; Interferon; Innate immunity