The diversity of STING in regulating immune cell function and its role in liver diseases: from bench to bedside

The cyclic guanosine monophosphate-adenylate synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical innate immune signaling pathway that recognizes and transmits cytoplasmic DNA signals, triggering interferon and inflammatory responses. Immune cells enriched in the liver participate in the development of various liver diseases through the STING pathway; however, the precise regulatory mechanisms of this pathway within the immune cells remain poorly integrated. Elucidating these mechanisms holds promise for developing novel therapeutic strategies to address related clinical challenges.

This review systematically elucidates the mechanisms by which immune cells from both innate and adaptive immune systems influence liver diseases via the STING pathway, viewed through the lens of immune cell classification. Considering the differential expression of STING across immune cell types and their cross-regulatory interactions, the review categorizes STING's impact on liver diseases into two patterns: direct regulation by endogenous STING (intracellular STING) and indirect regulation by exogenous STING (STING originating from other cells). The diseases discussed encompass common liver disorders, such as viral hepatitis, metabolic dysfunction-associated steatotic liver disease(MASLD), hepatocellular carcinoma(HCC), and autoimmune hepatitis (AIH),among others.Integrating the latest preclinical research findings, the review thoroughly explores the potential feasibility and research progress of targeting the STING pathway to modulate the progression of liver diseases, including traditional STING agonist/antagonist, and novel approaches such as targeted delivery systems and microbiotherapy in STING drug development, along with their therapeutic potential in liver diseases.

The cGAS-STING pathway serves as a pivotal signaling axis linking innate and adaptive immunity, playing a crucial role in the immune regulation of liver diseases. In-depth investigation of this pathway provides theoretical and translational foundations for elucidating the mechanisms underlying immune-metabolic dysregulation in the liver and developing precision immunotherapy strategies, thereby facilitating its transition from basic research to clinical treatment.