The cGAS-STING pathway: mechanistic basis, dual biological functions and translational therapeutic advances

The cGAS-STING pathway acts as a central and highly potent innate immune sensing system in the human body. It can efficiently recognize cytoplasmic double-stranded DNA originating from invading exogenous pathogens and damaged endogenous host cells. This unique molecular recognition feature lays a solid foundation for its multiple vital physiological functions, including host defense against infections, tumor immune surveillance, and the maintenance of normal cellular homeostasis. This review systematically investigates the distinct functional states and biological behaviors of the cGAS-STING pathway under a variety of disease conditions. When the pathway is activated properly at the right time and with appropriate intensity, it can effectively eliminate invasive pathogens and exert potent anti-tumor effects to restrain malignant progression. On the contrary, aberrant, excessive or long-term persistent activation of this signaling cascade will trigger severe inflammatory reactions, which further drive the onset and deterioration of autoimmune disorders, neurodegenerative diseases and multiple aging-related illnesses. Moreover, this article also summarizes the latest research progress of targeted agonists and inhibitors developed for this pathway. We elaborate on their application scenarios, core advantages and existing bottlenecks, aiming to provide comprehensive theoretical references and research directions for follow-up basic mechanistic studies and clinical transformation of cGAS-STING targeted therapeutic strategies.