Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING, also known as TMEM173) constitute the major signaling pathway in vertebrates that senses non-self DNA and elicits potent immune responses. At the core of this pathway, cGAS senses double-stranded DNA (dsDNA) and synthesizes cyclic GMP-AMP (cGAMP). cGAMP serves as a second messenger that relays its signal to downstream innate immune responses through STING. One of the major consequences triggered by the cGAS-STING pathway is the production of antiviral cytokines of the type I interferon family, which in turn induce expression of hundreds of interferon-stimulated genes (ISGs) with diverse antiviral functions. Recent studies have also revealed functional homologs across phylogenetic kingdoms with innate defense functions, suggesting an ancient evolutionary origin of cGAS-STING signaling. Aberrant activation of the cGAS-STING pathway by host DNA can lead to sterile inflammation associated with tissue damage, degeneration as well as premature aging. In this primer, we will introduce the basic principles of cGAS-STING signaling in the vertebrate system and highlight recent discoveries regarding its connection to other fundamental cellular processes in the context of human diseases.

Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes. cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity. At the same time, cGAS-STING signaling must be carefully regulated to maintain immune homeostasis. Interestingly, exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling, including cGAS condensates, STING condensates, and IRF3 condensates. In addition, several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling. These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery. Here, we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.

The cGAS-STING pathway plays a significant role in host defense against viral and bacterial infection. In the process, the cytoplasmic free DNA, considered as a danger signal, is recognized by nucleotidyl transferase cGAS. cGAS is activated by double-stranded DNA (dsDNA) and catalyzes the synthesis of a noncanonical cyclic dinucleotide 2'5'-cGAMP from adenosine triphosphate (ATP) and guanosine triphosphate (GTP). cGAMP serve as an endogenous second messenger to stimulate the induction of type I interferons via STING. In addition to the exogenous bacterial or viral DNA, abnormal deposition of host DNA in cytosol also activates the cGAS-STING signaling pathway cascade, resulting in inflammation and autoimmune diseases. Subsequent studies found that this pathway also plays an important role in tumor's responsiveness to radio-therapy and chemo-therapy. Activation of cGAS-STING pathway produces or enhances the therapeutic efficacy. These findings suggest that specifically interfering with cGAS-STING activation may hold therapeutic value for the treatment of cancer, infection and inflammatory diseases. In this paper, the activation mechanism of cGAS-STING pathway and its relationship with the treatment of diseases were summarized, and the regulation of cGAS-STING pathway was introduced in detail. Key words: cGAS-STING pathway; Regulation; Tumor therapy; Autoimmune disease

The cGAS-STING signaling pathway has emerged as a key mediator of inflammation. However, the roles of chloride homeostasis on this pathway are unclear. Here, we uncovered a correlation between chloride homeostasis and cGAS-STING signaling. We found that dysregulation of chloride homeostasis attenuates cGAS-STING signaling in a lysosome-independent manner. Treating immune cells with chloride channel inhibitors attenuated 2'3'-cGAMP production by cGAS and also suppressed STING polymerization, leading to reduced cytokine production. We also demonstrate that non-selective chloride channel blockers can suppress the NPC1 deficiency-induced, hyper-activated STING signaling in skin fibroblasts derived from Niemann Pick disease type C (NPC) patients. Our findings reveal that chloride homeostasis majorly affects cGAS-STING pathway and suggest a provocative strategy to dampen STING-mediated inflammation via targeting chloride channels.

The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.

DNA is highly immunogenic, both exogenous and endogenous DNA can activate the pathogen-associated molecular pattern (PAMP) and danger-associated molecular pattern (DAMP), respectively, and hence activate the evolutionarily conserved cGAS-STING pathway for inflammatory responses. The cGAS-STING signaling pathway plays a very important role in the pathogenesis and progression of neoplastic diseases. For cancer therapy, there are some discrepancies on whether cGAS-STING should be inhibited or activated. Deregulated cGAS-STING signaling pathway might be the origin and pathogenesis of tumor, understanding and modulating cGAS-STING signaling holds great promise for cancer therapy. In this review article, we discuss the molecular mechanisms underlying cGAS–STING deregulation, highlighting the tumor inhibiting and promoting roles and challenges with cGAS–STING agonists in the context of cancer therapies.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a critical innate immune pathway that, following engagement by DNA, promotes distinct immune effector responses that can impact virtually all aspects of tumorigenesis, from malignant cell transformation to metastasis. Here we address how natural tumor-associated processes and traditional cancer therapies are shaped by cGAS-STING signaling, and how this contributes to beneficial or detrimental outcomes of cancer. We consider current efforts to target the cGAS-STING axis in tumors and highlight new frontiers in cGAS-STING biology to inspire thinking about their connection to cancer.

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS–STING pathway. We critically evaluated the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, activating the cGAS–STING pathway. This activation prompts the production of proinflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS–STING pathway. Effective mitophagy might suppress the cGAS–STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS–STING pathway, potentially leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy–cGAS–STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, which could lead to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues in neurodegenerative disease research.

Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has great potential to promote antitumor immunity. Development of activators for the cGAS-STING pathway (cGAS-STING activators) has profoundly revolutionized tumor immunotherapy. However, successful clinical application of cGAS-STING activators is contingent on having appropriate systems to achieve safe, effective, and specific delivery. There is an increasing emphasis on the design and application of nano drug delivery systems (NDDS) that can facilitate the delivery potential of cGAS-STING activators. In this review, we discuss barriers for translational development of cGAS-STING activators (DNA damaging drugs and STING agonists) and recent advances of NDDS for these agents in tumor immunotherapy.

Stimulatorof interferon genes (STING) is an intracellular sensor of cyclic dinucleotides involved in the innate immune response against pathogen- or self-derived DNA. For years, interferon (IFN) induction of cyclic GMP-AMP synthase (cGAS)-STING has been considered as a canonical pattern defending the host from viral invasion. The mechanism of the cGAS-STING-IFN pathway has been well-illustrated. However, other signalling cascades driven by cGAS-STING have emerged in recent years and some of them have been found to possess antiviral ability independent of IFN. Here, we summarize the current progress on cGAS-STING-mediated nonclassic antiviral activities with an emphasis on the nuclear factor-κB and autophagy pathways, which are the most-studied pathways. In addition, we briefly present the primordial function of the cGAS-STING pathway in primitive species to show the importance of IFN-unrelated antiviral activity from an evolutionary angle. Finally, we discuss open questions that need to be solved for further exploitation of this field.