The bidirectional immunoregulatory effects of Traditional Chinese Medicine on the cGAS-STING signaling pathway and their translational prospects

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central component of innate immunity, mediating host defense against pathogens, antitumor responses, and inflammation. Aberrant activation of this pathway is implicated in a spectrum of diseases, including autoimmune disorders, chronic inflammation, organ injury, and metabolic dysregulation. Traditional Chinese Medicine (TCM), with its multi-component and multi-target characteristics, presents a promising strategy for modulating cGAS-STING signaling. Emerging evidence indicates that bioactive compounds, single herbs, herbal formulas, and related nanomedicines can bidirectionally regulate this pathway, either by directly targeting cGAS or STING or by influencing upstream processes such as DNA damage, mitochondrial dysfunction, and mitochondrial DNA (mtDNA) release. These interventions modulate inflammatory responses, immune cell activity, and disease progression. TCM does not regulate cGAS-STING signaling through a single pathway alone. The cGAS-STING pathway interacts with NF-κB signaling, NLRP3 inflammasome activation, MAPK pathways, oxidative stress, autophagy, ferroptosis, and pyroptosis. These interactions may help explain the multi-target and multi-pathway effects of TCM in immune regulation. Here, we review recent advances in understanding TCM-cGAS-STING interactions, highlighting their roles in infection, cancer, autoimmune disorders, and other complex diseases, and discuss the mechanistic insights and translational potential of TCM in immune modulation.