Immune system homeostasis is vital to overall health, as proper immune regulation ensures normal physiological functions, while dysregulation can lead to various diseases (1, 2). The innate immune system play a crucial role in recognizing pathogen-associated molecular patterns and danger-associated molecular patterns through pathogen recognition receptors. These receptors form as the first line of defense against bacterial and viral infections, as well as aseptic inflammatory, by triggering the production of pro-inflammatory and anti-viral cytokines (3).

The cGAS-STING signaling pathway, as an important element of innate immunity, has garnered significant attention in recent years for its role in maintaining immune system homeostasis (4). This pathway plays a crucial role in antitumor immunity, and inflammatory and infectious diseases, as it recognizes various sources of cytoplasmic DNA, including bacterial, viral, and mitochondrial DNA (5). Upon detection of cytoplasmic DNA, cGAS generates cyclic GMP-AMP (2′3′-cGAMP), which activates STING. This process leads to TANK-binding kinase 1 (TBK1) phosphorylation (pTBK1) and induces type I interferon (IFN-I) transcription (6–8). In antiviral infections, STING acts through an IFN-I-driven immune response (7, 9). Activation of cGAS-STING enhances the ability of immune cells to target antigens through multiple pathways, thereby defending against pathogen invasion (10, 11). However, structural or functional abnormalities in this pathway may also contribute to the development of autoimmune and inflammatory diseases, such as systemic lupus erythematosus (SLE) and non-alcoholic fatty liver disease (NAFLD). Although cGAS is able to sense double-stranded DNA (dsDNA), it is unable to distinguish between its own DNA and exogenous DNA (12). Prolonged stimulation of aberrant DNA can lead to the overactivation activation of the STING pathway, resulting in excessive synthesis and release of IFN-I and inflammatory cytokines, which drive the progression of inflammatory or autoimmune diseases (13). In addition, tumor-derived dsDNA activates the STING pathway in antigen-presenting cells, promoting interferon production. This process facilitates dendritic cell maturation, T cell recruitment, and enhances anti-tumor responses (14).

Traditional Chinese Medicine (TCM) has a long history, traditionally employed for the prevention and treatment of a wide spectrum of diseases. Studies have shown that TCM has a bidirectional regulatory effect in immunomodulation, both activating the immune system and suppressing excessive immune responses (15). For example, ginseng contains a variety of active ingredients (e.g., ginsenosides, ginseng polysaccharides) that have immunomodulatory effects. A randomized controlled trial showed that ginseng polysaccharide for 8-14 weeks enhanced the cytotoxic activity of NK cells and up-regulated serum TNF-α levels (16). TCM has been associated with potential benefits in adjunct cancer therapy, particularly in alleviating clinical symptoms, extending patient survival, and modulating immune functions (17–19). TCM principles identify ‘yang deficiency’ as the underlying cause of breast cancer. The classic anti-neoplastic formula, Yanghe Decoction (YHD), has been shown in contemporary research to decrease myeloid-derived suppressor cells (MDSCs) and suppress the tumor microenvironment’s iNOS and ARG-1 expression. At the same time, it enhances the immune response by increasing the number of natural killer T cells (NKTs) and CD4 T cells (20). Unlike chemotherapy, traditional Chinese medicine (TCM) not only directly targets tumor cells but also effectively boosts the immune response. For instance, the TCM formula Shugan Jianpi Decoction has been shown to suppress the proliferation of MDSCs and enhance the inflammatory regulatory functions of NKT cells (21). In addition, certain herbal components, such as astragaloside derived from Huangqi (Radix Astragali), can significantly promote IFN-γ secretion from T cells and enhance T cell immunoreactivity (22).

Increasing attention has been given to the immunomodulatory potential of TCM, particularly the ability of TCM active compounds or formulations to address diseases such as inflammation, infection, and cancer, by modulating the cGAS-STING signaling pathway ( Figure 1 ). By regulating this pathway, Chinese medicines may enhance the body’s immune response to pathogens and tumors, as well as inhibit excessive immune responses. However, these effects are primarily observed in preclinical studies investigating underlying mechanisms of disease treatment. Further well-designed clinical trials are necessary to confirm these findings.

Despite the growing recognition of the cGAS-STING signaling pathway’s significance in immunomodulation, comprehensive reviews on how TCMs target this pathway remain scarce. This paper aims to address this gap by summarizing recent advancements in understanding the cGAS-STING pathway’s role in immune regulation and the potential mechanisms underlying herbal interventions. The findings are expected to serve as a valuable reference for future in-depth mechanistic research.

Innate immunity serves as the body’s first line of defense against invading pathogens (23). The stimulator of interferon genes (STING) is a critical protein that mediates various DNA receptors in this system. STING, also referred to as ERIS, MYPS, and MITA, is a conserved transmembrane protein encoded by the TMEM173 gene. Predominantly localized in the endoplasmic reticulum, it is also found on Golgi and mitochondrial membranes (24). STING consists of 379 amino acids and contains an N-terminal transmembrane region and a C-terminal cytoplasmic globular structural domain, which interacts with another STING molecule to form an intact dimer (25).

STING detects cytoplasmic dsDNA and serves as a direct sensor for endogenous cyclic dinucleotides (CDNs) (26). Activation of cGAS, a nucleotidyltransferase that senses cytoplasmic non-self DNA, catalyzes the production of 2′3′-cGAMP, a CDN composed of adenosine and guanosine ( Figure 2 ) (27, 28). In addition to cGAMP, STING can be triggered by bacterial-derived CDNs, such as cyclic di-AMP and cyclic di-GMP (29). CDNs and 2′3′-cGAMP bind to STING in the endoplasmic reticulum, facilitating the dimerization and translocation of STING to the perinuclear region (29, 30). STING recruits TBK1 and IκB kinase (IKK) during translocation, which then relocates to the perinuclear region. These kinases phosphorylate interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), which activates the expression of IFN-I and pro-inflammatory cytokines (31–33). IFN-I enhances immune responses by promoting the activation and function of immune cells such as dendritic cells, T cells, and natural killer cells (34).

The cGAS-STING pathway is a conserved innate immune mechanism that responds to pathogenic infections, DNA damage, and aberrant cell activities like uncontrolled replication or senescence (35). In cancer therapy, activation of STING enhances tumor antigen presentation and promotes antitumor immunity, making it an attractive immunotherapeutic target (36). Studies have shown that cGAS-STING agonists not only induce tumor cell senescence but also boost adaptive anticancer immunity and combine efforts with immunotherapy (37, 38). Clinical trials have explored two main types of STING agonists: cyclic dinucleotides (CDNs, e.g., ADU-S100) and non-CDN (e.g., DMXAA) (39, 40). For instance, ADU-S100, the first CDN derivative in clinical trials, has demonstrated the ability to stimulate IFN-β production by human immune cells, showcasing its therapeutic potential (41). Additionally, cGAS activity is critical for the success of immune checkpoint blockade therapies, with STING agonists showing promise in enhancing vaccine efficacy for tumors resistant to PD-1 inhibitors (42).

In addition to cancer therapy, the cGAS/STING pathway plays a vital role in viral infections. Many DNA viruses, such as herpes simplex virus (HSV) and hepatitis B virus (HBV), are able to inhibit viral replication by initiating IFN-I production through activation of this pathway (43, 44). This suggests that STING agonists may have broad-spectrum antiviral potential (45). For example, DMXAA is a potent antiviral agent in mice; α-Mangostin, a flavonoid with antimicrobial properties, has been shown to possess antiviral properties and anti-DENV and HBV replicative activity in cellular experiments (46–48). However, numerous viruses such as HSV, Human CMV (HCMV), etc. have evolved mechanisms to circumvent this pathway (49–51). For instance, Epstein-Barr virus (EBV) suppresses localized innate immunity by targeting STING for degradation through the E3 ubiquitin ligase TRIM29 (52).

However, despite its protective roles, excessive activation of STING can lead to autoimmune conditions like Aicardi-Goutières syndrome (AGS) and SLE (53–55). In these diseases, both autologous DNA and mitochondrial DNA may be misrecognized by cGAS, leading to the activation of STING and an excessive IFN-I response (56). To address this, inhibitors targeting STING or cGAS have emerged as therapeutic candidates. Compounds like Acrinamin and Oxychloroquine show potential in blocking cGAS activation, offering new avenues for treating autoimmune disorders (57).

Although several STING agonists and inhibitors have been developed, they have had limited effect in clinical translation. TCM offers a valuable resource for the development of STING modulators, including inhibitors and activators. This underscores TCM’s potential to address various diseases through immunomodulatory mechanisms, providing a robust foundation for future research and drug development ( Figure 2 ).

Chinese medicines play a vital bidirectional role in immunomodulation, both activating the immune system and suppressing excessive immune responses. This regulation is achieved by influencing various aspects such as immune cells, cytokines, and immune organs. Studies have shown that certain Chinese medicines can effectively regulate the production of immune cells and cytokines (58, 59). Certain herbal medicines boost innate immune system activity, while others act on cellular subpopulations of adaptive immunity (60).

Chinese medicines act by enhancing the function of various immune cells, including macrophages, dendritic cells, NK cells, T cells, and B cells. For example, Ganoderma lucidum polysaccharide (PS-G), the primary active compound in Ganoderma lucidum, has been shown to promote activation and maturation of dendritic cells derived from human monocytes (61). Herbal medicines also regulate T lymphocyte activity by stimulating their proliferation and differentiation, promoting cytotoxic T lymphocyte production, and modulating the TH1/TH2 balance as well as the function of T helper (TH) cell subsets (59). For example, polysaccharides from Cordyceps sinensis enhance the expression of transcription factors such as T-bet, GATA-3, and RoR-γt in TH cells, thereby increasing the number of TH1, TH2, and TH17 cells (62). B lymphocytes, the main cells of humoral immunity, depend on antigen stimulation to release antibodies (63). Research indicates that polysaccharides from Dendrobium huoshanense and Atractylodes macrocephala Koidz significantly increase B lymphocyte populations, thereby strengthening humoral immunity (64, 65).

In addition, herbal medicines can regulate the production of specific cytokines, including interferons (IFN-α, IFN-β, IFN-γ), tumor necrosis factor (TNF-α), and interleukins (e.g., IL-1, IL-2, IL-4), which are pivotal in immune and inflammatory processes. For example, polysaccharides from Atractylodes macrocephala and Astragalus membranaceus markedly upregulated IFN-γ expression in vitro experiments (66, 67).

The diversity of immunomodulatory components in TCM provides a wide range of therapeutic potential for clinical applications. These components are mainly divided into two categories: anti-inflammatory and immune-enhancing. The anti-inflammatory category includes phenolic acids (e.g., vanillic acid, salvianolic acid B), flavonoids (e.g., luteolin, glabridin), volatile oils (e.g., perillaldehyde, zingiber officinale), lignans (e.g., schisandrin C, asarinin), and alkaloids (e.g., rocaglamide, tetrandrine), while the immune-enhancing category mainly consists of polysaccharides (e.g., lycium barbarum polysaccharides, astragalus membranaceus polysaccharides) and glycosides (e.g., ginsenoside Rg3, ginsenoside Rd) (68–72). These components regulate the body’s immune response through different pathways, enabling TCM to demonstrate unique advantages in the treatment of immune-related diseases.

Additionally, TCM is closely related to the concept of “medicine and food,” i.e., certain species offer both nutritional benefits and therapeutic effects (73). With the growing emphasis on preventive care and holistic health in recent years, many TCM ingredients have been incorporated into daily diets as functional foods or dietary supplements and have become an important part of alternative therapies (74, 75).

In recent years, activators and inhibitors of the cGAS-STING pathway have attracted widespread attention, but clinical translation still faces challenges. TCM, as a valuable cultural heritage of the Chinese nation, has shown promising potential in modulating immune-related diseases. Several active compounds have been found to effectively modulate the cGAS/STING signaling pathway and improve diseases. These include ginsenoside Rg3 and ginsenoside Rd, which are derived from Panax ginseng; glabridin and licochalcone B, obtained from Glycyrrhiza uralensis; perillaldehyde, isolated from Perilla frutescens; and schisandrin C, extracted from Schisandra chinensis ( Figure 2 ). Natural products have been valued as indispensable resources for discovering novel therapeutic molecules and are instrumental in managing diseases (76–78). The mechanisms and clinical applications of TCM in modulating this pathway will be summarized below, categorized by different types of diseases.

Due to their multi-component and multi-target characteristics, traditional quality control methods have difficulty comprehensively assessing the safety and efficacy of Chinese medicines (181–183). To cope with these challenges, biomarkers have shown significant potential as tools for quality evaluation of TCM in recent years. Using technologies such as metabolomics, biomarkers can more comprehensively assess the systemic effects and compatibility of TCM. The components of schisandrol A, schisandrin A, gomisin N, and schisandrin B can be used as biomarkers for evaluating the quality standard of Schisandra chinensis (Turcz.) Baill (184). In addition, biomarkers can evaluate the clinical efficacy of TCM, such as NF2 and PPP1CA in CDDP, which are thought to be associated with its vasodilatory effects (185).

Biomarkers are equally important in disease treatment. In viral infections, IFN, a central factor in the antiviral response, has emerged as a potential therapeutic target for infections such as HCV and HBV (186). IL-6 plays an important role in the acute inflammatory response, and changes in its level correlate with the severity of infection. Especially in COVID-19, elevated IL-6 levels are closely associated with disease progression, suggesting its potential as a marker for monitoring treatment efficacy (187).

The cGAS-STING pathway is an important part of the innate immune system and has emerged as a potential therapeutic target for a variety of diseases in recent years (188–190). cGAS recognizes intracellular DNA and activates STING proteins, which in turn initiates downstream signaling pathways and induces antiviral and pro-inflammatory factors (191). cGAS-activated signaling molecules, such as TBK1 and IRF3, play a key role in immunoregulation (10). These proteins are not only key regulators of disease progression, but they may also be important biomarkers for evaluating therapeutic effects.

Traditional Chinese medicine plays an immunomodulatory role in the treatment of many diseases by modulating the cGAS-STING pathway. For example, total glucosides of paeony can alleviate liver inflammation caused by acute liver injury by inhibiting the STING-IRF3 interaction (142). Tetrahydroxy stilbene glucoside from Polygonum multiflorum was found to reduce neuroinflammation by inhibiting the cGAS-STING pathway, thereby improving cognitive function in patients with Alzheimer’s disease (164). In addition, ginsenoside Rb3 was effective in ameliorating ischemia-reperfusion injury in skin flap transplantation by inhibiting the STING-mediated inflammatory response (179). These studies demonstrated the modulatory effects of TCM on key proteins in the cGAS-STING pathway, suggesting that these proteins can be used as biomarkers of TCM therapy for assessing efficacy and potential for individualized treatment.

In summary, key proteins such as cGAS, STING, TBK1, and IRF3 play important roles in the occurrence and development of diseases. By regulating the expression and activity of these proteins, TCM can effectively regulate immune responses and treat a variety of diseases. Therefore, the key proteins in the cGAS-STING pathway can not only be used as targets for TCM to regulate immune and inflammatory responses, but they also have the potential to serve as biomarkers for clinical therapeutic effects. This provides a new direction for the future application of TCM in precision medicine.

TCM holds an important position in the field of medicine due to its unique bidirectional immunomodulatory ability, which can activate the immune system to enhance the body’s defense, while also moderately inhibiting excessive immune responses and reducing inflammation and autoimmune diseases. The cGAS-STING pathway, an important component of the innate immune system, plays a key role in defending against viral and bacterial infections, modulating cellular damage, inflammatory responses, autophagy, and tumor immunity (56, 192). Therefore, the cGAS-STING pathway has become a potential drug target for treating inflammatory diseases, tumors, and immune dysregulation. TCM has shown unique potential in modulating this pathway, providing new strategies for the treatment of a variety of diseases.

Currently, the development of activators and inhibitors of the cGAS-STING pathway is a research priority. Although STING agonists have shown promising results in preclinical antitumor studies, their clinical translation faces many challenges. For example, modified CDN compounds are rapidly degraded in vivo due to poor metabolic stability, which affects the durability of their efficacy (193). In addition, the low cellular uptake rate of CDN makes it difficult for the drug to efficiently enter target cells, which in turn limits its antitumor effects (194). While most studies rely on intra-tumor drug delivery, there is a lack of delivery technologies that can be applied on a large scale, further limiting the potential application of STING agonists in clinical therapy. In addition, the limited targeting of STING agonists may lead to off-target effects, triggering unnecessary immune activation and increasing autoimmune risks (195). Thus, improving the targeting and safety of STING agonists remains a critical issue for realizing their clinical applications. Regarding STING inhibitors, although compounds such as H-151, C-176, BB-Cl-amidine, and sulforaphane have been reported to inhibit the activation of the cGAS-STING pathway, their therapeutic potential remains limited (196–200). H-151, as the most promising STING inhibitor, inhibits palmitoylation by binding to the Cys91 site of the STING protein (196). However, studies on it are still at the animal experiment stage. Therefore, the development of clinically applicable STING inhibitors in inflammatory and autoimmune diseases remains an urgent topic.

Chinese medicines show remarkable potential in modulating the cGAS-STING pathway, especially in the treatment of inflammatory diseases. For example, compounds such as perilla aldehyde, ursodeoxycholic acid, total glucosides of paeony, and andrographolide affect the activity of this pathway through different mechanisms. Perillaldehyde has been shown to inhibit the innate immune response induced by cytosolic DNA by inhibiting cGAS activity and to attenuate the inflammatory response by reducing the release of inflammatory factors through inhibition of downstream signaling after STING activation. Ursodeoxycholic acid, on the other hand, inhibits the production of pro-inflammatory cytokines by blocking PANoptosis-like cell death through inhibition of the STING pathway. Various active components in licorice, such as glabridin, licorice flavonoids, and licorice chalcone B, can inhibit cGAS-STING-mediated inflammatory responses by modulating the cGAS-STING pathway, thereby exerting therapeutic effects on inflammatory diseases. TRIM29 has been reported to contribute to the pathogenesis of viral myocarditis by enhancing ROS-mediated oxidation of TBK1, thereby inhibiting its function (201). Both TRIM29 and TRIM18 play pivotal roles in the progression of various virus infections, including viral enteritis, viral myocarditis, and various organ inflammations (52, 202, 203). Studies suggest that TCM, with its rich repertoire of antiviral herbal compounds (such as quercetin and ginsenosides), may offer therapeutic potential in treating these infectious diseases. TCM may modulate immune responses by downregulating the expression of TRIM29 and TRIM18, thereby mitigating the inflammatory damage caused by these viral infections. These findings provide important clues for the development of novel herbal therapies based on the cGAS-STING pathway and open up new directions for immunomodulation in a variety of diseases.

Studying the targeting of the cGAS-STING pathway by TCM reflects the unique advantages of TCM in immunomodulation, providing both a scientific basis for modernizing traditional medicine and a new strategy for immunotherapy. However, while studies have demonstrated the potential of TCM in modulating the cGAS-STING pathway, more high-quality research is needed to validate these effects for true clinical applications. Meanwhile, an in-depth understanding of the mechanism of action of TCM can help promote the modernization of TCM and enhance its value for clinical application (204). In the future, with in-depth studies on the mechanisms of the cGAS-STING pathway, TCM may become an effective tool for modulating immune and inflammatory responses, bringing new hope for the treatment of a variety of diseases.