Xi Chen
Xiaohua Tang3†
Yang Ye
Fei Mao- 1Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- 2Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, China
- 3The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Jiangsu University, Zhenjiang, Jiangsu, China
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a critical mechanism of DNA sensing in innate immunity. Activation of this pathway can induce the production of interferons and proinflammatory cytokines. In the intestine, this pathway exhibits bidirectional regulatory properties, with appropriate activation maintaining homeostasis and inhibiting tumorigenesis, while excessive activation leads to inflammatory responses. A thorough exploration of the molecular mechanisms and regulatory networks of the cGAS-STING signaling pathway offers a significant theoretical foundation and potential treatment targets for developing novel strategies to treat intestinal diseases. This review summarizes the most recent developments on the function of the cGAS-STING regulatory pathway in colorectal tumors and inflammatory bowel disease. It discusses targeted therapeutic approaches that interfere with this pathway.
1 Introduction
The intestinal mucosal immune system is the core regulator of intestinal homeostasis. It achieves adaptive responses to commensal microorganisms and food-borne antigens by precisely balancing immune defense and immune tolerance. Disruption of this immune homeostasis can trigger chronic inflammatory responses and increase the risk of tumorigenesis (1–3). In recent years, the role of the innate immune system in the pathogenesis of intestinal diseases has attracted considerable attention. Among them, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, as a key pathway for cytoplasmic DNA sensing, plays an important regulatory role in infection, inflammation, and tumorigenesis (4, 5). cGAS is a key molecule in cytoplasmic DNA sensing that can specifically recognize exogenous pathogens (such as viruses and bacteria) and endogenous damage-related (such as mitochondrial and nuclear sources) double-stranded DNA (dsDNA) (5, 6). Upon activation, it catalyzes the synthesis of 2'3'-cyclic GMP-AMP (cGAMP) from adenosine triphosphate (ATP) and guanosine 5'-triphosphate (GTP). It promotes the binding of cGAMP to STING, thereby cascadingly activating the nuclear factor-kappaB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways, eventually inducing the transcriptional expression of type I interferons and proinflammatory cytokines (7, 8).
With the recent expansion of studies on gut immune modulation, the cGAS-STING transduction pathway has become increasingly prominent in the pathophysiology of gastrointestinal conditions, including colorectal cancer (CRC) and inflammatory bowel disease (IBD). It is also worth noting that existing studies have shown that this pathway participates in the maintenance of intestinal homeostasis through a dual regulatory mechanism (9, 10). Therefore, thorough analysis of the molecular processes and networks that regulate the cGAS-STING axis in IBD and CRC will improve our understanding of the pathophysiology of these conditions and provide a basis for developing new, personalized treatment strategies (11, 12). However, the specific regulatory processes and translational applications of this route in intestinal diseases still face significant challenges. This review summarizes the latest advances in the role of the cGAS-STING signaling pathway in IBD and CRC and describes targeted therapeutic strategies targeting this signaling pathway.
2 The signaling pathway of cGAS-STING
2.1 DNA sensing by cGAS
DNA activates the cGAS-STING signaling pathway. When cGAS identifies exogenous or endogenous dsDNA, it promotes the synthesis of cGAMP. cGAMP activates a series of downstream signaling pathways, such as the type I interferon and NF-κB pathways, by binding to STING, thereby promoting inflammation (13, 14). cGAS-STING signaling has effects at the cellular level on autophagy, translation, metabolic homeostasis, cell concentration, DNA damage repair, aging, and cell death (15). Simultaneously, the cGAS-STING axis plays a crucial role in innate immunity and viral defense by detecting DNA (16).
2.2 STING activation and downstream signaling and effector functions
cGAS is a crucial enzyme implicated in sensing cytoplasmic DNA, possessing a nucleotide transferase domain along with two DNA-binding domains. As the critical functional domain of cGAS, the C-terminal nucleotidyltransferase (NTase) domain consists of a catalytic domain and two positive regions. When cGAS detects DNA from microbes such as viruses, retroviruses, or bacteria, or from self-DNA (17), the DNA ligand binds to cGAS in a minimum 2:2 combination, causing alteration in conformation in cGAS, which catalyzes ATP and GTP into 2',3'-cGAMP (16, 18, 19). At this point, a second messenger, cGAMP, attaches itself to the DNA-sensing hub STING, triggering a protein conformational change that leads to STING oligomerization into a tetramer. The endoplasmic reticulum (ER) transfers STING oligomers to the Golgi apparatus. Within the ER-Golgi intermediate compartment (ERGIC) of the Golgi apparatus, STING is palmitoylated and recruits serine/threonine protein kinase 1 (TBK1) (20). TBK1 transphosphorylates STING's C-terminal domain, recruiting the transcription factor IRF3 for stimulation, resulting in IRF3 dimerization and migration to the cell nucleus, inducing the release of type I IFN, with IFN-β being the primary type I IFN. Additionally, the STING signal can also phosphorylate IκBα (an NF-κB inhibitory protein) via TBK1 or the IKK complex, leading to its ubiquitination and breakdown, which releases NF-κB (21). Free NF-κBtranslocates to the cell nucleus, initiating the expression of cytokine genes, such as tumor necrosis factor (TNF), IL-6, and IL-1β (15, 17). After activation, STING is transported to the endolysosome for degradation (22). Figure 1 illustrates the activity of the cGAS-STING pathway during innate immune responses.
Figure 1. The cGAS-STING pathway's activation during innate immunological reactions. Following the identification of DNA from external and intracellular sources, cGAS dimers aggregate on dsDNA and catalyze the formation of 2',3'-cGAMP from ATP and GTP. cGAMP then binds to STING dimers in the ER, triggering STING oligomerization and releasing it from anchor factors. STING then enters COPII vesicles. As STING passes through the ERGIC and the Golgi apparatus, it attracts TBK1, promotes the transphosphorylation of STING by TBK1, and recruits IRF3. Consequently, IRF3 dimerizes and moves into the nucleus, inducing the release of type I interferons. STING activation also leads to the ubiquitination and breakdown of IκBα, releasing NF-κB. Following its translocation to the nucleus, NF-κB produces TNF, IL-6, IL-1β, and other chemicals. Finally, STING in the autophagosome and Golgi apparatus is transported to the lysosome for degradation. ATP, adenosine triphosphate; cGAMP, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate; COPII, coat protein complex II; dsDNA, double-stranded DNA; cGAS, cyclic GMP-AMP synthase; ER, endoplasmic reticulum; ERGIC, ER-Golgi intermediate compartment; IL, interleukin; IκBα, inhibitor of nuclear factor kappa B alpha; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor-kappaB; STING, stimulator of interferon genes; TBK1 serine/threonine protein kinase 1; TNF, tumor necrosis factor.
2.3 Regulation of the cGAS-STING pathway
The cGAS-STING pathway is positively and negatively regulated by cellular components and enzymes, as well as additional DNA-sensing routes (9, 10). For example, the nucleic acid enzyme DNase II in lysosomes digests DNA in endosomes or autophagosomes, thereby preventing DNA from entering the cytoplasm and inhibiting cGAS activation. Three-prime repair exonuclease 1 (TREX1) is an exonuclease that degrades DNA in the cytoplasm. Defects in TREX1 are associated with various autoimmune and inflammatory diseases, including Aicardi-Goutieres syndrome and systemic lupus erythematosus, among others (23). Additionally, cGAS downstream ligands, like cGAMP and STING, can adversely affect cGAS activity by modifying it through processes such as sumoylation, phosphorylation, deubiquitination, glutamylation, and phosphodiesterase-catalyzed hydrolysis. Positive regulation of the cGAS-STING pathway is primarily achieved through post-translational cellular regulators via modification, direct interaction, or indirect assistance (4). Table 1 summarizes the intracellular modulators of cGAS, cGAMP, and STING activity.
Table 1. Intracellular regulators that enhance or inhibit cGAS, cGAMP, and STING activity.
2.4 The cGAS-STING pathway's various biological roles and disease implications
The cGAS-STING route functions as the core molecular mechanism for cytoplasmic DNA sensing, contributing significantly to cellular homeostasis and immunological surveillance under physiological conditions. Dysfunction in this pathway is closely linked to the onset and progression of various conditions. Existing studies indicate that this signaling pathway not only mediates the classical IFN-I response but also participates in the control of multiple critical cellular biological processes through a multi-level molecular regulatory network. This pathway can trigger autophagy by activating TBK1 and autophagy-related proteins (such as ULK1 and Beclin-1) (44), thereby maintaining intracellular homeostasis and clearing pathogens or abnormal protein aggregates. Additionally, STING activation disrupts the ER membrane structure, inducing ER stress, and influences cell survival and death decisions through the unfolded protein response (UPR) (45). Furthermore, the signaling pathway of cGAS-STING can promote DNA damage repair by regulating repair factors, such as ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), contributing significantly to the preservation of genomic stability (46). Persistent activation of the cGAS-STING pathway may drive cellular senescence or programmed cell death through the p53/p21 or NF-κB pathways (46). Numerous studies have shown that the cGAS-STING signaling pathway plays a key regulatory role in the onset and progression of various diseases, including viral infections (47–49), metabolic endocrine disorders (50–52), autoimmune diseases (53–55), and neurological disorders (44, 55). Figure 2 depicts how the cGAS-STING axis functions in cellular homeostasis and under various conditions.
Figure 2. The cGAS-STING route in cellular homeostasis and diseases. The cGAS-STING route bidirectionally regulates cellular homeostasis and inflammation, balancing immune defense and disease onset. cGAS, cyclic GMP-AMP synthase; DNA, deoxyribonucleic acid; ER, endoplasmic reticulum; STING, stimulator of interferon genes.
3 The cGAS-STING signaling pathway in IBD
3.1 Overview of IBD
IBD is a chronic inflammatory disease of the gastrointestinal tract, primarily consisting of two subtypes: Crohn's disease (CD) and ulcerative colitis (UC) (56). Its clinical manifestations include gastrointestinal symptoms such as abdominal pain, diarrhea, fever, and rectal bleeding, as well as extraintestinal manifestations such as arthritis, osteoporosis, and psoriasis, and are often accompanied by cardiovascular diseases, metabolic syndrome, and cancer (57, 58). Epidemiological studies indicate that the incidence of IBD continues to rise, has gradually evolved into a global disease, and has severely impacted quality of life for patients (59). The development of IBD is affected by multiple factors, and recent research on its pathogenesis has made substantial progress, involving abnormalities in the gut microbiota, immune dysregulation, environmental changes, and genetic mutations. Numerous studies indicate that IBD's main cause is the interplay between microbes and the host. When the host has susceptible genes, it is prone to disrupting microbial homeostasis, allowing pathogens to invade the intestines, triggering destructive immune responses, inducing persistent inflammation, and promoting the progression of IBD (60). From an immunological perspective, Th17 cells are considered a primary pathogenic factor in IBD, playing a central role in the induction and maintenance of chronic intestinal inflammation in IBD patients (61). Th17 cells are extensively infiltrated in IBD patients' inflammatory intestinal mucosa, and the quantity of cells that release cytokines associated with Th17 and IL-17 is also increased in inflammatory tissues, in contrast to healthy tissues (8).
The gut mucosa gets exposed to both potentially harmful and commensal bacteria. The intestinal barrier serves as the first line of defense against intestinal microbiota. The gut microbiota is made up of immunological cells (such as intraepithelial lymphocytes, or IELs), differentiated epithelial cells and their secretory components (including mucins from goblet cells and antimicrobial peptides from Paneth cells), and stem cells (62). IECs are an indispensable component of the intestinal barrier, providing both physical and biochemical barriers to separate microorganisms from host tissues and maintain intestinal homeostasis. Homeostasis of the intestinal mucosa depends on the local immune system to maintain tolerance toward the normal microbiota and initiate effective immune responses to eradicate intestinal pathogens. An effective barrier function includes maintaining epithelial integrity, mucus layer production, and antimicrobial peptide secretion (63).
3.2 The dual role of cGAS-STING signaling in gut homeostasis and inflammation
In a healthy environment, the interaction between gut microbes and the colon mucosa relies on the STING signaling pathway in both epithelial and immunological cells. Canesso and colleagues reported that, compared with control mice, systemic STING gene-knockout (STING-/-) mice showed reduced levels of TCRαβ-type IELs, goblet cells, mucins (MUC1 and MUC2), and secretory immunoglobulin A (sIgA) in the colon, which was accompanied by a marked alteration in gut microbial composition, characterized by an increase in pro-inflammatory bacteria (e.g., Desulfovibrio) and a decrease in beneficial taxa such as Allobaculum and Bifidobacterium (64). There was an increase in innate lymphoid cells 1 (ILC1) and ILC3 and a reduction in ILC2 and Treg cells in the lamina propria, indicating enhanced intestinal inflammatory responses and impaired immune regulatory function in these mice. Additionally, compared with the control group, these STING-deficient mice exhibited significantly increased susceptibility to colitis and Salmonella typhimurium infection. These findings collectively indicate that a STING deficit increases vulnerability to intestinal inflammation and bacterial infections in mice, underscoring STING's role as an important modulator of gut homeostasis (64). In intestinal immunity, stimulation of interferon (type I, IFN-I) secretion and interferon-stimulated genes (ISGs) enhances the epithelium barrier's regrowth and integrity (65, 66), encourages goblet cells to produce mucus, Paneth cells to produce antimicrobial peptides, and plasma cells to synthesize and secrete sIgA (9). This beneficial partnership is essential for maintaining the balance of immunological cells and fostering a healthy and harmonious intestinal environment (9). Figure 3 illustrates the role of cGAS-STING signaling in maintaining immune homeostasis and establishing intestinal microbial balance.
Figure 3. The function of cGAS-STING signaling activity in health. In a healthy environment, the symbiotic interaction between the gut’s microbes and the mucosa of the colon depends on the regulation of the endogenous STING pathway in host epithelial cells and innate immune cells. Activating the STING pathway significantly increases the expression of IFN-I and ISGs. This stimulation helps renew and maintain the integrity of the epithelial barrier, enhances the production of antimicrobial peptides by Paneth cells, boosts mucus production by goblet cells, and increases the synthesis of sIgA by plasma cells. Together, these effects synergistically strengthen the host's defense against pathogenic infections. This mutually beneficial relationship serves a crucial regulatory function in preserving immunological homeostasis and establishing intestinal microecological balance. DNA,deoxyribonucleic acid; cGAS, cyclic GMP-AMP synthase; cGAMP,2'3'-cyclic GMP-AMP; STING, stimulator of interferon genes; IFN-I, type I interferons; ISGs, interferon-stimulated genes; sIgA, secretory IgA; AMPs, antimicrobial peptides.
Although STING plays a crucial function in preserving intestinal mucosal homeostasis, excessive activation of the cGAS-STING signaling pathway induces intestinal inflammation. IBD manifests as dysbiosis induced by epithelial barrier damage, with pathogenic microorganisms crossing the intestinal epithelial biological barrier and migrating into the lamina propria (LP), where they are recognized by immune cells, triggering local and systemic immune responses (8). Accumulating evidence suggests that cell-free DNA exerts a pro-inflammatory effect in IBD. Elevated mitochondrial DNA (mtDNA) levels in plasma have been consistently demonstrated in both dextran sulfate sodium (DSS)-induced murine colitis models and clinical cohorts of ulcerative colitis (UC) and Crohn's disease (CD) patients, with mtDNA concentrations showing significant positive correlation with disease severity (67, 68). Enhanced DNA damage and cytosolic DNA accumulation were consistently detected in colonic tissues from both experimental colitis models and IBD patients (69). Shmuel-Galia et al. (70), studying mice with STING gain-of-function Sting+/N153s (N153S), discovered that in contrast to the control category, the mice exhibited weight loss, shorter colon length, and compromised integrity of the intestinal barrier, specifically manifested by increased intestinal permeability, reduced ZO-1 levels, goblet cell loss and its byproducts (MUC2 and trefoil factor 3), decreased intestinal lymphocytes, and increased production of defensins and regenerating islet-derived protein 3-gamma. This indicates that the intestinal barrier in mice is severely damaged, immune responses are disrupted, and excessive activation of STING contributes to the onset and exacerbation of IBD. Figure 4 shows the function of stimulation of cGAS-STING signaling in exacerbating intestinal inflammatory responses.
Figure 4. The function of cGAS-STING signaling activity in intestinal inflammation. In an inflammatory environment, dysbiosis of the microbiota and disruption of the epithelial barrier lead to the migration of harmful microbes into the LP. Both internal and external DNA stimulate the cGAS-STING transduction route in epithelial and immunological cells, promoting infiltration and activation of macrophages and inducing T cell aggregation and immune activation of dendritic cells (DCs), thereby exacerbating intestinal inflammatory responses. Additionally, STING activation and its downstream factors induce ER stress and apoptosis, further exacerbating barrier dysfunction. cGAS, cyclic GMP-AMP synthase; cGAMP,2'3'-cyclic GMP-AMP; ER,endoplasmic reticulum; IFN-I, Type I Interferons; ISGs, interferon-stimulated genes; LP, lamina propria; STING, stimulator of interferon genes.
3.3 Extracellular vesicle-mediated DNA signaling and the cGAS-STING pathway in IBD
STING stimulation in immunological and epithelial cells can be triggered by cell DNA, cyclic dinucleotides (CDNs), and self-DNA from damaged cells, including nuclear (genomic) DNA (ncDNA) and mtDNA. These events can worsen intestinal mucosal inflammation (8, 9). Intracellular DNA (such as mtDNA or nuclear DNA) can bind to specific proteins, forming complexes that are encapsulated in microvesicles (mEVs) and then taken up by distant cells. Studies have shown that self-DNA from intestinal epithelial cells (IECs) can be transported via extracellular vesicles (EVs) to macrophages, activating the cGAS-STING signaling pathway and triggering inflammation in IBD (1, 71). Within the digestive system, EVs are primarily secreted by immunological cells and IECs. IEC EVs interact with dendritic cells (DCs), stimulating the maturation of DCs, Tregs, and macrophages with tolerogenic properties through immune regulatory signals, playing a crucial role in regulating intestinal mucosal and epithelial barrier function (72, 73). Microbial EV-host cell communication is abundant in intestinal mucosal tissues. Microbial-derived EVs can influence microbial composition and metabolism by transmitting signaling molecules, thereby regulating intestinal microbial balance and maintaining intestinal homeostasis. However, in the intestines of patients with IBD, EVs can facilitate communication between microbes and host cells, impacting the onset and progression of the disease (74, 75). Microbial DNA in extracellular vesicles (mEVs) is a primary cause of inflammation and damage to barrier functions. Gut microbiota-derived mEVs regulate inflammatory responses by entering host cells with bacterial products. Nie and the team studied IBD patients and colitis mice, discovering that microbial DNA in the gut is carried by mEVs that infiltrate the mucosa. This triggers the cGAS-STING signaling pathway, reducing intestinal barrier function and enhancing inflammatory responses (76). IBD patients exhibit significantly reduced complement receptor of the immunoglobulin family positive macrophages (CRIg+Mφ), allowing mEVs to diffuse into the mucosa (76). Blocking the cGAS-STING activation pathway reduces inflammation resulting from CRIg+Mφ deficiency and mEV leaking (74). Consequently, mEVs that harbor microbial DNA and the absence of CRIg+Mφ induce inflammation in IBD, with the cGAS-STING pathway being pivotal (76).
3.4 cGAS-STING pathway and autophagy interaction in IBD and intestinal epithelial homeostasis
Apart from promoting cytokine expression, numerous studies have demonstrated that STING activation can also trigger autophagy, a process that is crucial for the antimicrobial defense of the intestinal mucosa. The autophagy pathway can degrade misfolded proteins and protein aggregates as well as other damaged cellular components, thereby mediating the capture and killing of intracellular pathogens (77).cGAS can directly interact with the key autophagy protein Beclin-1, thus, activating the Beclin-1–phosphatidylinositol 3-kinase class III (PI3KC3) autophagy complex and inducing autophagy (78).Khan and colleagues found that cGAS promotes autophagy by upregulating Beclin-1, reduces IEC death, and plays an important role in maintaining intestinal epithelial homeostasis during human IBD and mouse colitis (79).Furthermore, upon binding to cGAMP, STING then translocates to the ERGIC and Golgi apparatus, where it recruits the PI3P effector protein WIPI2 and the ATG5-ATG12-ATG16L complex, providing a membrane source for LC3 lipidation (microtubule-associated protein 1A/1B-light chain 3B) and initiating non-canonical autophagy (77, 80). STING activation can also trigger endoplasmic reticulum stress, which in turn, negatively regulates the mTOR signaling pathway to induce autophagy (78). Interestingly, another study showed increased STING protein expression in a DSS-induced colitis mouse model (81). This observation further supports an association between STING upregulation and modulation of autophagy during intestinal inflammation. Further research indicates that autophagy can also disrupt STING signaling, thereby limiting STING-dependent IFN-I production. Typically, to prevent excessive activation of the cGAS-STING pathway, downstream signals are transiently activated, after which autophagolysosomes degrade cGAS-STING (82).In chronic intestinal inflammation and autophagy dysfunction caused by genetic factors, excessive STING signaling leads to more severe intestinal tissue damage and inflammation (83). STING signaling and autophagy interact and regulate each other to maintain cellular immunological homeostasis and antimicrobial defense.
3.5 cGAS-STING signaling and its role in cellular death pathways and IBD
Beyond its immunoregulatory functions, the cGAS-STING signaling pathway also participates in diverse cell death-related processes, encompassing cellular senescence, lysosome-dependent cell death (LCD), pyroptosis, apoptosis, and necroptosis. When DNA-containing bacteria invade cells, the cGAS-STING pathway becomes activated, leading to an IFN-I immune response. Excessive secretion of IFN-I overactivates the p53-p21signaling pathway elevatesp16INK4 levels, accelerating cellular senescence and inhibiting cellular function (84). The cGAS-STING signaling pathway upregulates NLRP3 expression through IRF3-mediated mechanisms. Activation of the NLRP3 inflammasome promotes the secretion of mature caspase-1 and IL-1β, ultimately triggering potassium efflux and pyroptosis (85). Notably, activated caspase-1 interacts with cGAS, thereby inhibiting IFN production (28). Butyrate alleviates the occurrence of Crohn's disease by inhibiting the cGAS-STING-NLRP3 axis-mediated pyroptosis in intestinal epithelial cells (86). Simultaneously, STING also contributes to lysosome-dependent cell death. Subsequent studies have shown that STING, after activating downstream signaling cascades, translocates into lysosomes, leading to lysosomal membrane permeabilization (LMP) and the leakage of lysosomal proteases into the cytoplasm (85, 87). However, the specific mechanisms remain unclear and require further investigation. In addition to pyroptosis, STING can directly bind phosphorylated TBK1, activating IRF3, which then binds to Bax and translocates to mitochondria, inducing cytochrome c release and thereby triggering apoptosis (88). Phosphorylated IRF3 can also activate caspase-8, cleave BCL-2, and induce Bax and Bak to promote apoptosis (88). Zhou et al. demonstrated that macrophage extracellular traps activate the cGAS-STING pathway, leading to enhanced apoptosis and reduced expression of tight junction proteins, thereby exacerbating DSS-induced colitis (89).Additionally, cGAS-STING senses intracellular DNA, signal through IFN-I and TNF receptors, activate RIPK3 in myeloid-derived macrophages, and subsequently induce necrotic apoptosis (90, 91). Thus, the cGAS-STING pathway activation promotes macrophage invasion and stimulation, as well as T cell accumulation in the LP, leading to a persistent imbalance of pro-inflammatory cells and cytokines in IBD, thereby exacerbating inflammatory damage.
3.6 ER stress and its impact on the cGAS-STING transduction pathway
Research indicates that numerous factors can influence the cGAS-STING signaling pathway (4). Among these, ER stress has garnered increasing attention in recent years. Disruption of ER homeostasis may impair STING signaling in IECs, weakening their anti-infective and inflammatory regulatory capabilities in the gut, and this leads to impaired immune defense function and the onset of IBD (92). ER stress refers to the excessive accumulation of misfolded or unfolded proteins within the ER (93). Intractable ER stress activates STING, and excessive STING signaling disrupts calcium balance, causing T cells to overreact to ER stress-induced responses, ultimately leading to cell death. This results in inflammation through the release of pro-inflammatory cytokines, impaired antimicrobial defense, or induced cell death (94–96). Becker and colleagues found that ER stress promotes cellular regulation of amino acid transport and mitochondrial 1C metabolism to enhance redox balance, thereby maintaining cellular proliferation and immune function (97). Chronic ER stress-induced glutathione (GSH) metabolic remodeling serves a key role in the antioxidant and viral immune responses of IEC (90). However, prolonged stress leads to depletion of the antioxidant system, impairing the cGAS-STING activation immune pathway and increasing susceptibility to viral infections (e.g., Cytomegalovirus (CMV)) (97). Inhibiting ROS accumulation induced by ER stress restores STING activity and antiviral responses. This study demonstrates the potential clinical value of antioxidant therapy in intestinal inflammation and viral control (97).
In summary, STING is essential for preserving the homeostasis of the intestinal mucosa. However, excessive activation of the cGAS-STING signaling pathway can lead to inflammatory responses, exacerbate intestinal tissue damage, and encourage the onset of IBD. Notably, in addition to the cytoplasmic discharge of self-DNA due to cellular damage or stress, microbial DNA transmitted by extracellular vesicles (mEVs) is also an important cGAS-STING pathway inducer. STING signaling-induced autophagy plays an important role in the antimicrobial defense of the intestinal mucosa, and conversely, autophagy can also interrupt STING signaling to prevent its excessive activation. Additionally, the cGAS-STING pathway is involved in cell death pathways, including LDCP, apoptosis, and necroptosis. It is also known that the cGAS-STING signaling pathway is influenced by various factors (such as DNA properties, regulatory proteins, viral interference, and cellular state). Further research into these factors and their mechanisms may uncover new clinical applications.
4 The cGAS-STING signaling pathway in CRC
CRC is among the most prevalent cancerous growths worldwide, ranking second in cancer-related mortality and third in prevalence among all cancerous tumors, presenting a major risk to human life and well-being (98). CRC arises from tumor stem cells or cells that have stem cell-like properties. The development of CRC is driven not only by the accumulation of genetic alterations in cancer cells but also by immunosuppressive conditions within the tumor microenvironment (99). Studies have shown that reactive nitrogen and reactive oxygen species generated by inflammatory cells can cause alterations in important genes implicated in tumorigenesis. Additionally, specific inflammatory triggers, such as NF-κB and cyclooxygenase, are essential to the carcinogenic process (100). The cGAS-STING pathway influences CRC by regulating the intestinal epithelial barrier and enterocyte proliferation. Experimental studies in mice demonstrate that cGAS deficiency compromises epithelial barrier integrity, worsens inflammation, and increases tumor burden through STAT3 activation and immunosuppression (101). Moreover, STING deficiency elevates pro-inflammatory cytokine production, decreases IL-18 and IL-22 regulation, and impairs tissue repair, thereby promoting CAC progression (102). Consequently, chronic IBD can increase the risk of developing CRC (100).
Several investigations have shown that the signaling of cGAS-STING is essential for preventing the growth of tumors and maintaining the effectiveness of anti-tumor therapy. Activating the cGAS-STING signaling pathway could serve as a potential new therapeutic strategy for CRC. ThecGAS-STING pathway regulates various aspects of the cancer immune cycle, including tumor antigen release, antigen presentation, T cell activation, T cell transport and infiltration into tumor tissue, and T cell recognition and killing of tumor cells, exerting either anti-tumor or pro-tumor effects (103).Its activation can enhance tumor antigen presentation, promote the infiltration of effector T lymphocytes, and synergize with PD-1/PD-L1 immune checkpoint inhibitors (104).The stimulation of the cGAS-STING axis in cancerous cells usually arises from genetic instability or failures in DNA repair. Nuclear DNA leaking and development of extra-nuclear micronuclei are important mechanisms for cGAS activation. When micronuclei rupture, the DNA enclosed within them enters the cytoplasm (14), where cGAS binds to this DNA, catalyzing the synthesis of cGAMP and activating the STING pathway (105). As early as 2014, prior work by Woo et al.experimentally demonstrated that tumor-derived cytoplasmic DNA activates the host's cGAS-STING pathway, promoting IRF3-dependent IFN-β production, thereby stimulating the maturation of innate immune cells and promoting the development of an inflammatory milieu around a tumor (106). Both studies also indicated that mice lacking STING showed increased susceptibility to various malignant tumors and decreased survival rates, further highlighting the critical function of STING-mediated immunological reactions in the inhibition of tumors. Additionally, Ohkuri and team found that local application of STING agonists (c-di-GMP) amplifies IFN-I signaling and enhances cellular immunological reactions, demonstrating the role of STING agonists in anti-glioma immunotherapy and providing guidance for their clinical application in combination with tumor antigen vaccines (107). Notably, it was also found that DCs can phagocytose cGAMP derived from surrounding cells or tumor cells. The ingested cGAMP can be transported from endosomes to the cytoplasm, triggering the STING signaling cascade within DCs (108). In summary, STING stimulation promotes DCs, macrophages, CD8+ T cells, and NK cells to infiltrate, activate, proliferate, and cross-prime. This dual stimulation cascade effectively inhibits carcinogenesis by promoting pro-inflammatory immune responses in the tumor microenvironment (9). Figure 5 illustrates the function of the STING pathway in tumor suppression.
Figure 5. Role of STING pathway in tumor suppression. In early tumor precursor cells, the cGAS-STING pathway functions as a tumor suppressor, counteracting the carcinogenic effects induced by DNA damage. In tumor cells, cGAS can recognize cytoplasmic DNA that is produced by various sources of DNA damage. Activation of the cGAS-STING pathway upregulates the expression of type I interferons, ISGs, and SASP genes, as well as autophagy, thereby mediating tumor suppression. Furthermore, the cGAS-STING signaling pathway regulates anti-tumor immunological reactions by facilitating the interactions between immunological and tumor cells in the TME. cGAMP released by tumor cells and tumor-derived DNA can be taken up by APCs (such as DCs), thereby activating thecGAS-STING pathway, triggering the secretion of pro-inflammatory cytokines and IFN-I, and ultimately activating the tumor-killing functions of effector immunological cells, including NK and CD8+ T cells. This IFN-I-dependent mechanism significantly enhances the expression of CCR7 in APCs and their capacity for lymphatic migration, thus improving their efficiency in homing to draining lymph nodes. APC, antigen-presenting cell; DC, dendritic cells; DNA, deoxyribonucleic acid; ROS, reactive oxygen species; CIN,chromosomalinstability; cGAS, cyclic GMP-AMP synthase; cGAMP, 2'3'-cyclic GMP-AMP; STING, stimulator of interferon genes; IRF-3, interferon regulatory factor 3; IFN-I, Type I Interferons; ISGs, interferon-stimulated genes; SASP, senescence-associated secretory phenotype; SLC19A1, Solute carrier family 19 member 1; CCR7, C-C chemokine receptor type 7; TME, tumor microenvironment; NK, natural killer.
Numerous studies have demonstrated that the cGAS-STING pathway plays a pivotal role in CRC. cGAS-expressing cancer cells can identify cytoplasmic DNA and produce cGAMP (109), which can induce the STING pathway to stimulate the secretion of TNF-α and IFN-β, leading to substantial tumor cell necrosis (110).The mechanism of DNA mismatch repair (MMR) helps maintain DNA stability (100). During DNA damage, the MMR system facilitates cell cycle arrest and apoptosis, and its inactivation contributes to cancer (100).Previous research by Kaneta et al.analyzed public data and clinical tissue samples and found that the cGAS-STING signaling pathway is highly expressed in tumor cells of defective mismatch repair (dMMR)/microsatellite instability (MSI) CRC, and the stimulation of this process promotes the recruitment of CD8+ tumor-infiltrating lymphocytes and enhances the immune microenvironment (111). Experiments also showed that increased cGAS and STING expression in dMMR/MSI CRC is related to tumor immune activity and a better prognosis, and that downregulating the DNA repair gene MLH1 increases cGAS-STING pathway activation. This suggests that STING agonists may be suitable for treating CRC, and the high expression of the cGAS-STING pathway in dMMR/MSI CRC may provide a potential target for future immunotherapy (111). Nakajima and team found that approximately 60% of proficient DNA mismatch repair (pMMR) CRC cases simultaneously lack cGAS and STING expression (cGAS-/STING-), particularly in advanced tumors where STING expression is markedly reduced, possibly due to histone methylation regulation of the STING promoter region (112). Less than 10% of patients with pMMR and microsatellite stability (MSS) show cGAS+/STING+ expression, which correlates with increased infiltration of CD8+ and CD4+ T cells. Thus, cGAS-STING expression in tumor cells could be a useful indicator to forecast the success of immune checkpoint inhibitor (ICI) therapy in patients with pMMR/MSS CRC (112). Additionally, autophagy triggered by cGAS-STING stimulation can prevent the alteration of healthy cells into cancer cells by inducing cell death mediated by autophagy. This process responds to abnormal mitosis in healthy cells, eliminating cells that may undergo transformation and thereby protecting the body from the threat of carcinogenesis (113). However, the cGAS-STING axis enables tumor cells to avoid immunological detection. Certain cancer cell lines have STING and cGAS promoters that are susceptible to loss-of-function mutations or epigenetic silencing, which inhibits the cGAS-STING pathway (113).
As mentioned earlier, EVs can mediate communication between intestinal cells, maintain the gut mucosa barrier, participate in inflammatory processes, and regulate immune responses. Recently, mounting data have demonstrated that tumor-derived EVs also contribute significantly to the cGAS-STING regulatory cascade (114). Due to their small size, inherent biocompatibility, high physical and chemical stability (115), long-distance communication capabilities (115), and ease of interaction with cells (116), we can utilize gene engineering, metabolic labeling, and exogenous delivery technologies to modify EVs, which could open new avenues for nanomedicine (117). Exosomes are a specific subtype of EVs. Diamond et al. found that tumor cells secrete exosomes rich in ENPP1, which can hydrolyze extracellular cGAMP and cGAMP bound to LL-37, thereby inhibiting the cGAS-STING signaling pathway in immune cells (118). Using specific ENPP1 inhibitors can restore cGAS-STING activity and enhance anti-tumor immunity (114, 118). EVs are naturally occurring small vesicles that can deliver STING agonists such as cyclic dinucleotides to specific cells, including immune cells within the TME. STING agonists utilize the body's immunological system to identify and destroy cancer cells, playing a crucial role in cancer therapy. This approach not only enhances the efficacy of STING stimulation but also reduces systemic toxicity (119). ExoSTING is an exogenous cyclic dinucleotide-loaded engineered EV that can utilize the inherent ability of EVs to facilitate communication between APCs and tumor cells in the TME, directly delivering STING agonists to the TME to enhance local immune effects. Its key feature is prolonged retention in tumors, where it initially stimulates TME APCs, promoting local Th1 reactions, CD8+ T recruitment, and systemic defense against tumors, while reducing systemic inflammation. ExoSTING's precise delivery enhances drug targeting, improves stability and circulation time, reduces immune rejection and tolerance, and offers a therapy with a broader safety margin for cancer treatment (120).
Overall, the cGAS-STING axis inhibits the growth of tumors in CRC, and drugs that activate or modulate the cGAS-STING axis are being explored as a potential therapeutic strategy for CRC. Additionally, it is found that using EVs for the precise delivery of STING agonists can enhance local immune effects while reducing side effects, demonstrating the application potential of nanomedicine in drug delivery and immune regulation.
5 Treatment of IBD and CRC through targeting the cGAS-STING pathway
5.1 IBD
IBD, as a global disease with rapidly rising incidence rates, not only severely threatens human health but also imposes a heavy burden on individuals, families, and society (121). Conventional drug therapies are typically used to manage IBD, such as aminosalicylates (122), corticosteroids (123–126), immunomodulators (127, 128), and biologics (129). In certain instances, surgery is employed when necessary (130). In recent years, new therapies for IBD have surfaced, including monoclonal antibody therapy (131), microbiome modulation strategies (132), stem cell transplantation (133), and exosome treatment (134). However, these therapies are still in the research phase and face many challenges. Despite the availability of various treatment options for IBD, treatment outcomes remain suboptimal, necessitating the urgent development of new therapeutic approaches (92).
Targeted therapy has been widely adopted and represents a highly promising treatment strategy (135, 136). Considering the significance of the cGAS-STING signaling route in intestinal homeostasis and IBD, addressing it may provide a novel treatment approach. Ma et al. observed that Gasdermin D (GSDMD) is a negative regulator of the cGAS-STING signaling pathway in macrophages, and pharmacological inhibition of cGAS can reverse IBD symptoms in GSDMD-deficient mice (137). This confirms that GSDMD can control inflammation by inhibiting the cGAS-STING pathway, indicating that focusing on the GSDMD-cGAS signaling cascade may have potential value in the management of IBD (137). Additionally, developing novel oral nanomedicines by targeting the cGAS-STING signaling pathway has become a new direction in IBD treatment. Guilbaud and colleagues encapsulated the cGAS-STING inhibitor H-151 in lipid nanocapsules. This encapsulation induced the secretion of glucagon-like peptide-2 (GLP-2) and selectively targeted the cGAS-STING pathway along with its key downstream markers. As a result, it inhibited the expression of pro-inflammatory cytokines, promoted mucosal repair, and significantly reduced inflammatory responses in a mouse model of colitis. This method is highly selective, cost-effective, and scalable, offering great clinical application potential (138).
5.2 CRC
Numerous studies have highlighted the growing importance of the cGAS-STING signaling pathway in CRC, with targeting this pathway in CRC increasingly becoming a hot topic. The proper stimulation of immune cells' cGAS-STING pathway can inhibit tumor growth, while sustained activation may aid carcinogens in inducing tumor formation and blocking T cell-driven adaptive immunity (139). Chemotherapy and radiotherapy are well known for their effectiveness in halting the progression of cancer. Drugs that target and modulate this pathway may work in tandem with cGAS-STING agonists to reverse chemotherapy/radiotherapy resistance and improve clinical efficacy (3). Zhu et al. found that knocking down death-associated protein (Daxx) enhances the anti-tumor effects of chemotherapy drugs, while overexpressing Daxx reduces chemotherapy sensitivity (140). Additionally, Daxx inhibits the cGAS-STING activation pathway, weakening chemotherapy-induced immunogenic cell death (ICD) and anti-tumor immune reactions, thereby impairing the efficacy of chemotherapy in CRC. Targeting the Daxx/cGAS-STING axis could be a therapeutic strategy to improve chemotherapy efficacy in CRC patients (140). Li and colleagues demonstrated that phosphatidylinositol-3,4,5-trisphosphate RAC exchanger 2 (PREX2) overexpression is associated with CRC radiation resistance. PREX2 enhances DNA repair capacity by upregulating DNA-protein kinase, catalytic subunit (PKcs), prevents the induction of the radiotherapy-induced STING-IRF3-IFN signaling axis, and simultaneously weakens radiotherapy-induced ICD and CD8+ T cell infiltration (141). Additionally, targeting PREX2 inhibitors was found to reverse radiation resistance, enhance radiation sensitivity, and restore activation of the cGAS-STING-IFN pathway (141). In summary, PREX2 can be used as a marker to determine therapeutic targets and radiation therapy efficacy in CRC, and combining it with STING agonists can further synergistically enhance radiation therapy effects, providing a new direction for overcoming radiation resistance in CRC (141).
In addition to chemotherapy and radiotherapy, immunotherapy is emerging as a groundbreaking therapy modality, including ICIs, cancer vaccines, chimeric antigen receptor T-cell therapy, and tumor-infiltrating lymphocytes. For CRC, ICIs serve as the primary form of immunotherapy for populations with high MSI and dMMR (99). However, their effectiveness is limited in MSS populations (99). Notably, Duan and colleagues revealed that drug inhibition or gene knockout of protein arginine methyltransferase 6 (PRMT6) induces an MSI phenotype in MSS-CRC, characterized by MMR deficiency (142). PRMT6 deficiency causes increased infiltration of immunological cells, including NK and CD8+ T cells. Long-term inhibition of PRMT6 leads to the accumulation of cytoplasmic DNA, which activates the cGAS-STING route, thereby boosting anti-tumor immune responses (142). Additionally, it was found that combining PRMT6 inhibitors with programmed cell death protein 1 (PD-1) antibodies enhances sensitivity to immune checkpoint blockade therapy, significantly improving treatment efficacy and prolonging survival time in animal models (142). Targeting PRMT6 converts MSS-CRC into an MSI-like state, enhancing the effectiveness of immunotherapy and offering new insights and strategies for CRC treatment (142). Luo et al. discovered that gasdermin E (GSDME)-induced damage to the mitochondria activates the cGAS-STING-IFNβ route, leading to increased CD8+ T cell infiltration, which can synergize with ICIs, providing a potential new target for CRC treatment (143). Wu et al.demonstrated in vitro that RC48 not only induces cell cycle arrest but also significantly inhibits the proliferation of HER2-positive CRC by alleviating HER2-mediated immune suppression and turning on the cGAS-STING regulatory cascade, thus augmenting tumor susceptibility to anti-PD-1 immunotherapy (144). Furthermore, in vivo mouse models confirmed that the combination of RC48 with anti-PD-1 therapy significantly inhibits tumor growth and enhances anti-tumor immune responses, offering a new treatment option for HER2-positive CRC (144). As noted by Liu's research group, the synergistic effect of radiotherapy and ATR inhibitors (such as berzosertib) can stimulate the cGAS-STING-pTBK1/pIRF3 pathway by inhibiting SH2 domain-containing phosphatase 1 (SHP1) function, promoting T cell infiltration in colorectal tumors, transforming cold tumors into hot tumors, and improving immunity against tumors (145). Additionally, the combination of radiotherapy, berzosertib, and PD-1 inhibitors was found to significantly improve treatment outcomes in MSS-CRC, potentially offering a new therapeutic strategy for MSS-CRC (145). Lovastatin is a widely utilized hypolipidemic agent. Huang and colleagues found that lovastatin induces mitochondrial oxidative stress in human CRC cells, resulting in the cytoplasmic release of mtDNA, which triggers the cGAS-STING signaling pathway in HCT116 cells, ultimately inducing apoptosis and inhibiting the growth and proliferation of CRC cells (146). This study provides new potential targets and a theoretical basis for CRC treatment, as well as experimental support for the application of lovastatin in the field of anticancer therapy (146). The treatment approaches that alter the cGAS-STING pathway in IBD and CRC are summarized in Table 2.
Table 2. Targeted therapeutic strategies modulating cGAS-STING pathway in IBD and CRC.
6 Classification and mechanisms of cGAS-STING inhibitors and agonists
6.1 cGAS-STING inhibitors
Given the dual role of the cGAS-STING pathway in the pathogenesis and immune surveillance of IBD and CRC, appropriate targeted stimulation during disease progression can restore intestinal homeostasis and enhance anticancer immunity, demonstrating significant potential for clinical application. Inhibitors that downregulate the cGAS-STING pathway can mitigate the progression of autoimmune disorders and localized inflammation, and agonists that upregulate the cGAS-STING pathway can enhance immune system reactions and limit the entry of extracellular infections (4). Multiple studies have shown that inhibitors targeting the cGAS-STING signaling pathway play a key role in regulating innate immune responses. Recently, researchers have developed various specific inhibitors due to a better understanding of the molecular mechanisms involved in this pathway. Based on their target sites, these inhibitors can be categorized into two main classes: cGAS and STING inhibitors. cGAS inhibitors consist of DNA-competitive inhibitors and catalytic site inhibitors, while STING inhibitors include CDN-binding/conformation-regulating and STING palmitoylation modification inhibitors (147). As shown in Table 3, these drugs inhibit the cGAS-STING signaling axis through various mechanisms, offering new intervention targets for the future treatment of related diseases.
Table 3. cGAS or STING inhibitors.
6.2 cGAS-STING agonists
The cGAS-STING pathway is a central element of the innate immunological system, and its activation can induce strong IFN-I and pro-inflammatory cytokine responses, thereby enhancing anti-tumor immunity. In recent years, agonists of this pathway have emerged as a research hotspot due to their potential in tumor immunotherapy (147). These agonists can be classified into cGAS agonists and STING agonists based on their target sites. Table 4 summarizes the mechanisms of representative molecules and their functional roles in anti-tumor immunity. Since activating STING can initiate 2'3'-cGAMP, most STING activators are mimics of 2'3'-cGAMP synthesis, many of which undergo chemical changes to enhance their stability and resistance to hydrolysis. These modifications can extend their half-life in vivo, more effectively stimulate the STING pathway, activate immune responses, and thereby enhance anti-tumor effects (15). Such modified synthetic cGAMP holds significant potential in immunotherapy research and development (167). Previous studies have shown that the STING activator cGAMP plays a key role in activating the cGAS-cGAMP-STING-IRF3 pathway for anti-tumor effects. Li et al. found that cGAMP can promote cytokine production, activate dendritic cells, and drive T cell-mediated immune responses, demonstrating significant anti-tumor effects in a mouse colon adenocarcinoma model (168). Additionally, cGAMP can enhance the efficacy of the chemotherapy drug 5-FU while reducing its toxic side effects, demonstrating its potential as a novel immunotherapy drug in cancer treatment (168). Notably, the proportion of non-nucleotide small-molecule agonists has been increasing in recent years, as they offer advantages such as high oral bioavailability (161), long half-life (169), strong target specificity (147), and low production costs (147). For example, the non-nucleotide small-molecule agonist MSA-2 demonstrates significant tumor suppression and sustained immunotherapeutic effects when administered orally or via subcutaneous injection, and can selectively activate STING in tumors while reducing systemic toxicity. When combined with PD-1 ICIs, it improves effectiveness while maintaining good tolerability (161). Additionally, cancer vaccines based on STING agonists hold great application potential. For instance, STINGVAX effectively activates the cGAS-STING signaling pathway, stimulating innate and adaptive anti-tumor immune responses, and when combined with PD-1 blockers, it significantly enhances efficacy (170).
Table 4. cGAS or STING agonists in anti-tumor immunity.
In summary, given the crucial role of the cGAS-STING pathway in IBD and CRC, targeting and regulating the cGAS-STING axis has emerged as a potential therapeutic strategy for IBD and CRC. Combining this approach with radiotherapy, chemotherapy, CAR-T therapy, and other modalities can further enhance treatment efficacy. Currently, various inhibitors and agonists targeting the cGAS-STING axis have been created and are gradually being validated in preclinical studies or clinical trials. Several drugs targeting the cGAS-STING pathway have shown promise in treating IBD and CRC, as shown in Table 5. Although the cGAS-STING route shows great potential in anti-infection, inflammation regulation, and tumor immunity, there are still many shortcomings and challenges in terms of precise delivery, safety, and efficacy. Addressing these issues will not only promote the clinical translation of cGAS-STING pathway-targeted therapy but also provide insights for other immune regulation strategies.
Table 5. Drugs targeting the cGAS-STING pathway for the treatment of IBD and CRC.
7 Challenges and limitations
Despite significant progress in elucidating the role of the cGAS-STING pathway in IBD and CRC, several critical scientific questions and challenges remain unresolved in this field. For instance, while most studies have focused on immune cell components—such as macrophages, dendritic cells, natural killer cells, and T cells, the impact of non-immune cells (e.g., epithelial and stromal cells)and their functional contributions to intestinal diseases remains insufficiently supported by experimental evidence (9, 173). Expanding investigations to non-immune cell populations may help uncover intricate cell-cell interactions and provide novel insights for developing more cell-targeted therapeutic strategies and interventions. Additionally, preclinical research predominantly relies on genetically engineered mouse models, which exhibit substantial differences from humans in terms of intestinal anatomy, immune cell repertoire, and microbiome composition (177). Given the structural and regulatory divergence of cGAS-STING pathway components across species, more rigorous evaluation of preclinical drug candidates is warranted to ensure their translatability and applicability in clinical trials (178). Also, in the context of therapeutic applications, existing STING agonists/antagonists often suffer from poor tissue specificity and high systemic toxicity, with severe adverse events, including cytokine release syndrome and autoimmune-like reactions, previously reported in clinical trials (179). Moreover, both IBD and CRC exhibit considerable disease heterogeneity, with significant variations in cGAS-STING pathway activity across different molecular subtypes within the TME. However, reliable biomarkers for clinical subtyping and personalized treatment remain lacking. From a technical standpoint, the low abundance of pathway components in human tissue samples and the substantial interindividual variation in gut microbes further complicate the challenges of sensitivity in detection and mechanistic studies (180). Addressing these fundamental and translational challenges is a critical prerequisite for translating basic research on the cGAS-STING pathway into clinically viable therapies.
8 Conclusion and future perspectives
Recently, the cGAS-STING signaling pathway has garnered significant attention for its crucial role in regulating the innate immune response and is emerging as a promising therapeutic target for intestinal diseases. cGAS plays a critical role in host defense, inflammatory responses, and tumor immune regulation by recognizing exogenous and endogenous DNA. Studies have shown that extracellular vesicles (EVs) derived from microorganisms and tumors can activate the cGAS-STING pathway by delivering their specific DNA. Besides mediating the classic IFN-1 response, this pathway also regulates various biological processes, including autophagy, ER stress, and senescent cell death. The cGAS-STING signaling pathway has a "double-edged sword" effect in the intestinal environment. On one hand, normal activation levels of cGAS-STING help maintain homeostasis of the intestinal barrier and promote tumor-suppressing immune responses. On the other hand, extended periods of unusual activation can lead to excessive inflammation, resulting in damage to the intestinal epithelium and an imbalance in the immune microenvironment. As research into the cGAS-STING signaling pathway advances, the clinical development of targeted agents has gained significant attention. STING agonists can enhance the anti-tumor effects of CRC treatment, while pathway inhibitors may improve the clinical prognosis of IBD and certain colorectal carcinomas. We hope that in the future, more biomarker-based targeted regulatory strategies can be developed to advance their precise clinical application in IBD and CRC.
Author contributions
XC: Writing – original draft. XT: Funding acquisition, Writing – review & editing. SC: Writing – review & editing. YY: Writing – review & editing. FM: Conceptualization, Funding acquisition, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was sponsored by the Henan Provincial Natural Science Foundation Project (No. 252300420143), the Science and Technology Development Project of Henan Province in 2024 (No. 242102310081), the open topic project of Shangqiu Medical College in 2023 (No. KFKT23005), the Zhenjiang Science and Technology Plan (Social Development) (No: SH2024047) and the key research and development (social development) projects of the Innovation Special Fund of Danyang (No: SSF202304).
Acknowledgments
The schematic illustrations were created using Biorender.com.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Glossary
cGAS: Cyclic GMP-AMP synthase
STING: Stimulator of interferon genes
dsDNA: Double-stranded DNA
cGAMP: 2'3'-cyclic GMP-AMP
ATP: Adenosine triphosphate
GTP: Guanosine 5'-triphosphate
NF-κB: Nuclear factor-kappaB
IRF3: Interferon regulatory factor 3
CRC: Colorectal cancer
IBD: Inflammatory bowel disease
NTase: C-terminal nucleotidyltransferase
ER: Endoplasmic reticulum
ERGIC: ER-Golgi intermediate compartment
TBK1: Threonine protein kinase 1
IκBα: Inhibitor kappa B alpha
TNF: Tumor necrosis factor
TREX1: Three-prime repair exonuclease 1
COPII: Coat protein complex II
DNaseII: Deoxyribonuclease II
SAMHD1: SAM domain and HD domain-containing protein 1
AIM2: Absent in melanoma 2
AKT: Protein kinase B
FI16: Interferon-inducible protein 16
TRIM41: Tripartite motif-containing protein 41
ENPP1: Ectonucleotide pyrophosphatase/phosphodiesterase 1
AMFR: Autocrine motility factor receptor
MUL1: Mitochondrial E3 ubiquitin ligase 1
USP13: Ubiquitin-specific peptidase 13
ULK1: Unc-51 like autophagy activating kinase 1
UPR: Unfolded protein response
ATM: Ataxia telangiectasia mutated
ATR: Ataxia telangiectasia and Rad3-related
CD: Crohn's disease
UC: ulcerative colitis
sIgA: Secretory immunoglobulin A
MUC1: Mucins 1
ILC1: Innate lymphoid cells 1
IFN-I: Interferon I
ISGs: Interferon-stimulated genes
LP: Lamina propria
mtDNA: Mitochondrial DNA
DSS: Dextran sulfate sodium
CDNs: Cyclic dinucleotides
ncDNA: Nuclear DNA
mEVs: Microvesicles
LDCP: Lysosome-dependent pyroptosis
LMP: Lysosomal membrane permeabilization
GSH: Glutathione
CMV: Cytomegalovirus
APC: Antigen-presenting cell
DC: Dendritic cell
ROS: Reactive oxygen species
CIN: Chromosomal instability
SASP: Senescence-associated secretory phenotype
SLC19A1: Solute carrier family 19 member 1
CCR7: C-C chemokine receptor type 7
TME: Tumor microenvironment
NK: Natural killer
dMMR: Defective mismatch repair
MSI: Microsatellite instability
pMMR: Proficient DNA mismatch repair
MSS: Microsatellite stability
ICI: Immune checkpoint inhibitor
GSDMD: Gasdermin D
GLP-2: Glucagon-like peptide-2
Daxx: Death-associated protein
ICD: Immunogenic cell death
PREX2: Phosphatidylinositol-3,4,5-trisphosphate RAC exchanger 2
PKcs: Catalytic subunit
PRMT6: Protein arginine methyltransferase 6
PD-1: Programmed cell death protein 1
SHP1: SH2 domain-containing phosphatase 1
GSDME: Gasdermin E
mtROS: Mitochondrial reactive oxygen species
RT: Radiation therapy
pHER2: Phosphorylated HER2
NO2-FAs: Nitro-fatty acids
Cys: Cysteine
References
1. Ke X, Hu T, and Jiang M. cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers. FASEB J. (2022) 36:e22029. doi: 10.1096/fj.202101199R
2. Decout A, Katz JD, Venkatraman S, and Ablasser A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. (2021) 21:548–69. doi: 10.1038/s41577-021-00524-z
3. Samson N and Ablasser A. The cGAS–STING pathway and cancer. Nat Cancer. (2022) 3:1452–63. doi: 10.1038/s43018-022-00468-w
4. Zhou J, Zhuang Z, Li J, and Feng Z. Significance of the cGAS-STING pathway in health and disease. IJMS. (2023) 24:13316. doi: 10.3390/ijms241713316
5. Dvorkin S, Cambier S, Volkman HE, and Stetson DB. New frontiers in the cGAS-STING intracellular DNA-sensing pathway. Immunity. (2024) 57:718–30. doi: 10.1016/j.immuni.2024.02.019
6. Kim J, Kim H-S, and Chung JH. Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway. Exp Mol Med. (2023) 55:510–9. doi: 10.1038/s12276-023-00965-7
7. Sun Z and Hornung V. cGAS–STING signaling. Curr Biol. (2022) 32:R730–4. doi: 10.1016/j.cub.2022.05.027
8. Hopfner K-P and Hornung V. Molecular mechanisms and cellular functions of cGAS–STING signalling. Nat Rev Mol Cell Biol. (2020) 21:501–21. doi: 10.1038/s41580-020-0244-x
9. Yang Y, Wang L, Peugnet-González I, Parada-Venegas D, Dijkstra G, and Faber KN. cGAS-STING signaling pathway in intestinal homeostasis and diseases. Front Immunol. (2023) 14:1239142. doi: 10.3389/fimmu.2023.1239142
10. Dimitrov G, Ryffel B, Togbe D, and Quesniaux V. cGAS-STING DNA-sensing in inflammatory bowel diseases. Trends Mol Med. (2025) 31:165–80. doi: 10.1016/j.molmed.2024.10.002
11. Zhang B, Xu P, and Ablasser A. Regulation of the cGAS-STING pathway. Annu Rev Immunol. (2025) 43:667–92. doi: 10.1146/annurev-immunol-101721-032910
12. Tian X, Ai J, Tian X, and Wei X. cGAS-STING pathway agonists are promising vaccine adjuvants. Medicinal Res Rev. (2024) 44:1768–99. doi: 10.1002/med.22016
13. Khoo LT and Chen L. Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches. EMBO Rep. (2018) 19:e46935. doi: 10.15252/embr.201846935
14. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. (2012) 482:53–8. doi: 10.1038/nature10802
15. Kwon J and Bakhoum SF. The cytosolic DNA-sensing cGAS–STING pathway in cancer. Cancer Discov. (2020) 10:26–39. doi: 10.1158/2159-8290.CD-19-0761
16. Wang Y, Luo J, Alu A, Han X, Wei Y, and Wei X. cGAS-STING pathway in cancer biotherapy. Mol Cancer. (2020) 19:136. doi: 10.1186/s12943-020-01247-w
17. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. (2013) 153:1094–107. doi: 10.1016/j.cell.2013.04.046
18. Zhang J, Zhang L, Chen Y, Fang X, Li B, and Mo C. The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential. Front Immunol. (2023) 14:1273248. doi: 10.3389/fimmu.2023.1273248
19. Blest HTW and Chauveau L. cGAMP the travelling messenger. Front Immunol. (2023) 14:1150705. doi: 10.3389/fimmu.2023.1150705
20. Skopelja-Gardner S, An J, and Elkon KB. Role of the cGAS–STING pathway in systemic and organ-specific diseases. Nat Rev Nephrol. (2022) 18:558–72. doi: 10.1038/s41581-022-00589-6
21. Mohammadi S and Khorasani M. Implications of the cGAS-STING pathway in diabetes: Risk factors and therapeutic strategies. Int J Biol Macromol. (2024) 278:134210. doi: 10.1016/j.ijbiomac.2024.134210
22. Wottawa F, Bordoni D, Baran N, Rosenstiel P, and Aden K. The role of cGAS/STING in intestinal immunity. Eur J Immunol. (2021) 51:785–97. doi: 10.1002/eji.202048777
23. Gao D, Li T, Li X-D, Chen X, Li Q-Z, Wight-Carter M, et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci USA. (2015) 112:E5699–705. doi: 10.1073/pnas.1516465112
24. Xiao N, Wei J, Xu S, Du H, Huang M, Zhang S, et al. cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model. J Autoimmun. (2019) 100:84–94. doi: 10.1016/j.jaut.2019.03.001
25. Coquel F, Silva M-J, Técher H, Zadorozhny K, Sharma S, Nieminuszczy J, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature. (2018) 557:57–61. doi: 10.1038/s41586-018-0050-1
26. Zhu W, Zu X, Liu S, and Zhang H. The absent in melanoma 2 (AIM2) inflammasome in microbial infection. Clinica Chimica Acta. (2019) 495:100–8. doi: 10.1016/j.cca.2019.04.052
27. Corrales L, Woo S-R, Williams JB, McWhirter SM, Dubensky TW, and Gajewski TF. Antagonism of the STING pathway via activation of the AIM2 inflammasome by intracellular DNA. J Immunol. (2016) 196:3191–8. doi: 10.4049/jimmunol.1502538
28. Wang Y, Ning X, Gao P, Wu S, Sha M, Lv M, et al. Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection. Immunity. (2017) 46:393–404. doi: 10.1016/j.immuni.2017.02.011
29. Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, et al. Gasdermin D restrains type I interferon response to cytosolic DNA by disrupting ionic homeostasis. Immunity. (2018) 49:413–426.e5. doi: 10.1016/j.immuni.2018.07.006
30. Seo GJ, Yang A, Tan B, Kim S, Liang Q, Choi Y, et al. Akt kinase-mediated checkpoint of cGAS DNA sensing pathway. Cell Rep. (2015) 13:440–9. doi: 10.1016/j.celrep.2015.09.007
31. Grabosch S, Bulatovic M, Zeng F, Ma T, Zhang L, Ross M, et al. Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene. (2019) 38:2380–93. doi: 10.1038/s41388-018-0581-9
32. Almine JF, O’Hare CAJ, Dunphy G, Haga IR, Naik RJ, Atrih A, et al. IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes. Nat Commun. (2017) 8:14392. doi: 10.1038/ncomms14392
33. Jønsson KL, Laustsen A, Krapp C, Skipper KA, Thavachelvam K, Hotter D, et al. IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. Nat Commun. (2017) 8:14391. doi: 10.1038/ncomms14391
34. Zheng W, Zhou R, Li S, He S, Luo J, Zhu M, et al. Porcine IFI16 negatively regulates cGAS signaling through the restriction of DNA binding and stimulation. Front Immunol. (2020) 11:1669. doi: 10.3389/fimmu.2020.01669
35. Liu Z-S, Zhang Z-Y, Cai H, Zhao M, Mao J, Dai J, et al. RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses. Cell Biosci. (2018) 8:35. doi: 10.1186/s13578-018-0233-3
36. Chen M, Meng Q, Qin Y, Liang P, Tan P, He L, et al. TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses. Mol Cell. (2016) 64:105–19. doi: 10.1016/j.molcel.2016.08.025
37. Wang C, Guan Y, Lv M, Zhang R, Guo Z, Wei X, et al. Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses. Immunity. (2018) 48:675–687.e7. doi: 10.1016/j.immuni.2018.03.017
38. Luteijn RD, Zaver SA, Gowen BG, Wyman SK, Garelis NE, Onia L, et al. Author Correction: SLC19A1 transports immunoreactive cyclic dinucleotides. Nature. (2020) 579:E12–2. doi: 10.1038/s41586-020-2064-8
39. Du M and Chen ZJ. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science. (2018) 361:704–9. doi: 10.1126/science.aat1022
40. Thomsen MM, Skouboe MK, Møhlenberg M, Zhao J, De Keukeleere K, Heinz JL, et al. Impaired STING activation due to a variant in the E3 ubiquitin ligase AMFR in a patient with severe VZV infection and hemophagocytic lymphohistiocytosis. J Clin Immunol. (2024) 44:56. doi: 10.1007/s10875-024-01653-5
41. Ni G, Konno H, and Barber GN. Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci Immunol. (2017) 2:eaah7119. doi: 10.1126/sciimmunol.aah7119
42. Sun H, Zhang Q, Jing Y-Y, Zhang M, Wang H-Y, Cai Z, et al. USP13 negatively regulates antiviral responses by deubiquitinating STING. Nat Commun. (2017) 8:15534. doi: 10.1038/ncomms15534
43. Lu Q-B, Ding Y, Liu Y, Wang Z-C, Wu Y-J, Niu K-M, et al. Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy. J Advanced Res. (2023) 51:161–79. doi: 10.1016/j.jare.2022.10.014
44. Jiang G-L, Yang X-L, Zhou H-J, Long J, Liu B, Zhang L-M, et al. cGAS knockdown promotes microglial M2 polarization to alleviate neuroinflammation by inhibiting cGAS-STING signaling pathway in cerebral ischemic stroke. Brain Res Bull. (2021) 171:183–95. doi: 10.1016/j.brainresbull.2021.03.010
45. Soh L-J, Lee S-Y, Roebuck MM, and Wong P-F. Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy. Life Sci. (2024) 357:123112. doi: 10.1016/j.lfs.2024.123112
46. Zhao Y, Simon M, Seluanov A, and Gorbunova V. DNA damage and repair in age-related inflammation. Nat Rev Immunol. (2023) 23:75–89. doi: 10.1038/s41577-022-00751-y
47. Xu G, Liu C, Zhou S, Li Q, Feng Y, Sun P, et al. Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion. Mol Cell. (2021) 81:2823–2837.e9. doi: 10.1016/j.molcel.2021.05.002
48. Jin M, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat Commun. (2021) 12:6565. doi: 10.1038/s41467-021-26851-2
49. Moossavi M, Rastegar M, Moossavi SZ, and Khorasani M. Molecular function of cGAS-STING in SARS-coV-2: A novel approach to COVID-19 treatment. BioMed Res Int. (2022) 2022:6189254. doi: 10.1155/2022/6189254
50. Bai J and Liu F. The cGAS-cGAMP-STING pathway: A molecular link between immunity and metabolism. Diabetes. (2019) 68:1099–108. doi: 10.2337/dbi18-0052
51. Bai J, Cervantes C, Liu J, He S, Zhou H, Zhang B, et al. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway. Proc Natl Acad Sci USA. (2017) 114:12196–201. doi: 10.1073/pnas.1708744114
52. Bai J and Liu F. cGAS–STING signaling and function in metabolism and kidney diseases. J Mol Cell Biol. (2021) 13:728–38. doi: 10.1093/jmcb/mjab066
53. Chen R, Du J, Zhu H, and Ling Q. The role of cGAS-STING signalling in liver diseases. JHEP Rep. (2021) 3:100324. doi: 10.1016/j.jhepr.2021.100324
54. Motwani M, McGowan J, Antonovitch J, Gao KM, Jiang Z, Sharma S, et al. cGAS-STING pathway does not promote autoimmunity in murine models of SLE. Front Immunol. (2021) 12:605930. doi: 10.3389/fimmu.2021.605930
55. Chen K, Lai C, Su Y, Bao WD, Yang LN, Xu P-P, et al. cGAS-STING-mediated IFN-I response in host defense and neuroinflammatoryDiseases. CN. (2022) 20:362–71. doi: 10.2174/1570159X19666210924110144
56. Fabián O and Kamaradová K. Morphology of inflammatory bowel diseases (IBD). Cesk Patol. (2022) 58:27–37.
57. Gecse KB and Vermeire S. Differential diagnosis of inflammatory bowel disease: imitations and complications. Lancet Gastroenterol Hepatol. (2018) 3:644–53. doi: 10.1016/S2468-1253(18)30159-6
58. Argollo M, Gilardi D, Peyrin-Biroulet C, Chabot J-F, Peyrin-Biroulet L, and Danese S. Comorbidities in inflammatory bowel disease: a call for action. Lancet Gastroenterol Hepatol. (2019) 4:643–54. doi: 10.1016/S2468-1253(19)30173-6
59. Qiu P, Ishimoto T, Fu L, Zhang J, Zhang Z, and Liu Y. The gut microbiota in inflammatory bowel disease. Front Cell Infect Microbiol. (2022) 12:733992. doi: 10.3389/fcimb.2022.733992
60. Lee SH, Kwon JE, and Cho M-L. Immunological pathogenesis of inflammatory bowel disease. Intest Res. (2018) 16:26. doi: 10.5217/ir.2018.16.1.26
61. Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. (2008) 57:1682–9. doi: 10.1136/gut.2007.135053
62. Okumura R and Takeda K. Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Exp Mol Med. (2017) 49:e338–8. doi: 10.1038/emm.2017.20
63. Xu AT, Lu JT, Ran ZH, and Zheng Q. Exosome in intestinal mucosal immunity. J Gastro Hepatol. (2016) 31:1694–9. doi: 10.1111/jgh.13413
64. Canesso MCC, Lemos L, Neves TC, Marim FM, Castro TBR, Veloso É, et al. The cytosolic sensor STING is required for intestinal homeostasis and control of inflammation. Mucosal Immunol. (2018) 11:820–34. doi: 10.1038/mi.2017.88
65. Østvik AE, Svendsen TD, Granlund AVB, Doseth B, Skovdahl HK, Bakke I, et al. Intestinal epithelial cells express immunomodulatory ISG15 during active ulcerative colitis and crohn’s disease. J Crohn’s Colitis. (2020) 14:920–34. doi: 10.1093/ecco-jcc/jjaa022
66. Giles EM, Sanders TJ, McCarthy NE, Lung J, Pathak M, MacDonald TT, et al. Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease. Mucosal Immunol. (2017) 10:184–93. doi: 10.1038/mi.2016.44
67. Vrablicova Z, Tomova K, Tothova L, Babickova J, Gromova B, Konecna B, et al. Nuclear and mitochondrial circulating cell-free DNA is increased in patients with inflammatory bowel disease in clinical remission. Front Med. (2020) 7:593316. doi: 10.3389/fmed.2020.593316
68. Boyapati RK, Dorward DA, Tamborska A, Kalla R, Ventham NT, Doherty MK, et al. Mitochondrial DNA is a pro-inflammatory damage-associated molecular pattern released during active IBD. Inflammatory Bowel Dis. (2018) 24:2113–22. doi: 10.1093/ibd/izy095
69. Wu X, Chen X, Liu H, He Z-W, Wang Z, Wei L-J, et al. Rescuing Dicer expression in inflamed colon tissues alleviates colitis and prevents colitis-associated tumorigenesis. Theranostics. (2020) 10:5749–62. doi: 10.7150/thno.41894
70. Shmuel-Galia L, Humphries F, Lei X, Ceglia S, Wilson R, Jiang Z, et al. Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells. Immunity. (2021) 54:1137–1153.e8. doi: 10.1016/j.immuni.2021.05.008
71. Zhao F, Zheng T, Gong W, Wu J, Xie H, Li W, et al. Extracellular vesicles package dsDNA to aggravate Crohn’s disease by activating the STING pathway. Cell Death Dis. (2021) 12:815. doi: 10.1038/s41419-021-04101-z
72. Ayyar KK and Moss AC. Exosomes in intestinal inflammation. Front Pharmacol. (2021) 12:658505. doi: 10.3389/fphar.2021.658505
73. Shen Q, Huang Z, Yao J, and Jin Y. Extracellular vesicles-mediated interaction within intestinal microenvironment in inflammatory bowel disease. J Advanced Res. (2022) 37:221–33. doi: 10.1016/j.jare.2021.07.002
74. Bittel M, Reichert P, Sarfati I, Dressel A, Leikam S, Uderhardt S, et al. Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo. J Extracellular Vesicle. (2021) 10:e12159. doi: 10.1002/jev2.12159
75. Ocansey DKW, Zhang L, Wang Y, Yan Y, Qian H, Zhang X, et al. Exosome-mediated effects and applications in inflammatory bowel disease. Biol Rev. (2020) 95:1287–307. doi: 10.1111/brv.12608
76. Nie S, Zhang Z, Ji Y, Ding Q, Gong J, Xiao F, et al. CRIg+ macrophages deficiency enhanced inflammation damage in IBD due to gut extracellular vesicles containing microbial DNA. Gut Microbes. (2024) 16:2379633. doi: 10.1080/19490976.2024.2379633
77. Glick D, Barth S, and Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. (2010) 221:3–12. doi: 10.1002/path.2697
78. Zheng W, Xia N, Zhang J, Chen N, Meurens F, Liu Z, et al. How the innate immune DNA sensing cGAS–STING pathway is involved in autophagy. Int J Mol Sci. (2021) 22:13232. doi: 10.3390/ijms222413232
79. Khan S, Mentrup HL, Novak EA, Siow VS, Wang Q, Crawford EC, et al. Cyclic GMP-AMP synthase contributes to epithelial homeostasis in intestinal inflammation via Beclin-1-mediated autophagy. FASEB J. (2022) 36:e22282. doi: 10.1096/fj.202200138R
80. Gui X, Yang H, Li T, Tan X, Shi P, Li M, et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature. (2019) 567:262–6. doi: 10.1038/s41586-019-1006-9
81. Martin GR, Blomquist CM, Henare KL, and Jirik FR. Stimulator of interferon genes (STING) activation exacerbates experimental colitis in mice. Sci Rep. (2019) 9:14281. doi: 10.1038/s41598-019-50656-5
82. Gonugunta VK, Sakai T, Pokatayev V, Yang K, Wu J, Dobbs N, et al. Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep. (2017) 21:3234–42. doi: 10.1016/j.celrep.2017.11.061
83. Mouna L, Hernandez E, Bonte D, Brost R, Amazit L, Delgui LR, et al. Analysis of the role of autophagy inhibition by two complementary human cytomegalovirus BECN1/Beclin 1-binding proteins. Autophagy. (2016) 12:327–42. doi: 10.1080/15548627.2015.1125071
84. Yu Q, Katlinskaya YV, Carbone CJ, Zhao B, Katlinski KV, Zheng H, et al. DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep. (2015) 11:785–97. doi: 10.1016/j.celrep.2015.03.069
85. Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell. (2017) 171:1110–1124.e18. doi: 10.1016/j.cell.2017.09.039
86. Xu X, Huang Z, Huang Z, Lv X, Jiang D, Huang Z, et al. Butyrate attenuates intestinal inflammation in Crohn’s disease by suppressing pyroptosis of intestinal epithelial cells via the cGSA-STING-NLRP3 axis. Int Immunopharmacol. (2024) 143:113305. doi: 10.1016/j.intimp.2024.113305
87. Wang F, Gómez-Sintes R, and Boya P. Lysosomal membrane permeabilization and cell death. Traffic. (2018) 19:918–31. doi: 10.1111/tra.12613
88. Cui Y, Zhao D, Sreevatsan S, Liu C, Yang W, Song Z, et al. Mycobacterium bovis induces endoplasmic reticulum stress mediated-apoptosis by activating IRF3 in a murine Macrophage Cell line. Front Cell Infect Microbiol. (2016) 6:182. doi: 10.3389/fcimb.2016.00182
89. Zhou Z, Miao X, Shen Y, Wang P, Shi R, Fan H, et al. Macrophage extracellular traps impair intestinal barrier function in DSS-induced colitis in mice by inducing intestinal epithelial cell apoptosis. Biochem Pharmacol. (2025) 242:117406. doi: 10.1016/j.bcp.2025.117406
90. Tang C-HA, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, et al. Agonist-mediated activation of STING induces apoptosis in Malignant B cells. Cancer Res. (2016) 76:2137–52. doi: 10.1158/0008-5472.CAN-15-1885
91. Brault M, Olsen TM, Martinez J, Stetson DB, and Oberst A. Intracellular nucleic acid sensing triggers necroptosis through synergistic type I IFN and TNF signaling. J Immunol. (2018) 200:2748–56. doi: 10.4049/jimmunol.1701492
92. Larabi A, Barnich N, and Nguyen HTT. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy. (2020) 16:38–51. doi: 10.1080/15548627.2019.1635384
93. Chen X, Shi C, He M, Xiong S, and Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Sig Transduct Target Ther. (2023) 8:352. doi: 10.1038/s41392-023-01570-w
94. Deuring JJ, Fuhler GM, Konstantinov SR, Peppelenbosch MP, Kuipers EJ, De Haar C, et al. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn’s disease. Gut. (2014) 63:1081–91. doi: 10.1136/gutjnl-2012-303527
95. Ma X, Dai Z, Sun K, Zhang Y, Chen J, Yang Y, et al. Intestinal epithelial cell endoplasmic reticulum stress and inflammatory bowel disease pathogenesis: an update review. Front Immunol. (2017) 8:1271. doi: 10.3389/fimmu.2017.01271
96. Wu J, Chen Y-J, Dobbs N, Sakai T, Liou J, Miner JJ, et al. STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death. J Exp Med. (2019) 216:867–83. doi: 10.1084/jem.20182192
97. Becker B, Wottawa F, Bakr M, Koncina E, Mayr L, Kugler J, et al. Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut. iScience. (2024) 27:109173. doi: 10.1016/j.isci.2024.109173
98. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, and Wallace MB. Colorectal cancer. Lancet. (2019) 394:1467–80. doi: 10.1016/S0140-6736(19)32319-0
99. Luo Y, Liang G, Zhang Q, and Luo B. The role of cGAS-STING signaling pathway in colorectal cancer immunotherapy: Mechanism and progress. Int Immunopharmacol. (2024) 143:113447. doi: 10.1016/j.intimp.2024.113447
100. Khorasani M. Role of cGAS-STING in colorectal cancer: A new window for treatment strategies. Cytokine. (2024) 173:156422. doi: 10.1016/j.cyto.2023.156422
101. Hu S, Fang Y, Chen X, Cheng T, Zhao M, Du M, et al. cGAS restricts colon cancer development by protecting intestinal barrier integrity. Proc Natl Acad Sci U.S.A. (2021) 118:e2105747118. doi: 10.1073/pnas.2105747118
102. Zhu Q, Man SM, Gurung P, Liu Z, Vogel P, Lamkanfi M, et al. STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol. (2014) 193:4779–82. doi: 10.4049/jimmunol.1402051
103. Tian Z, Zeng Y, Peng Y, Liu J, and Wu F. Cancer immunotherapy strategies that target the cGAS-STING pathway. Front Immunol. (2022) 13:996663. doi: 10.3389/fimmu.2022.996663
104. Khorasani M and Alaei M. cGAS-STING and PD1/PDL-1 pathway in breast cancer: a window to new therapies. J Recept Signal Transduct Res. (2024) 44:1–7. doi: 10.1080/10799893.2024.2325353
105. Xia T, Konno H, Ahn J, and Barber GN. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. (2016) 14:282–97. doi: 10.1016/j.celrep.2015.12.029
106. Woo S-R, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MYK, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. (2014) 41:830–42. doi: 10.1016/j.immuni.2014.10.017
107. Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, David M, et al. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res. (2014) 2:1199–208. doi: 10.1158/2326-6066.CIR-14-0099
108. Huang M, Cha Z, Liu R, Lin M, Gafoor NA, Kong T, et al. Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies. Front Immunol. (2024) 15:1399926. doi: 10.3389/fimmu.2024.1399926
109. Garland KM, Sheehy TL, and Wilson JT. Chemical and biomolecular strategies for STING pathway activation in cancer immunotherapy. Chem Rev. (2022) 122:5977–6039. doi: 10.1021/acs.chemrev.1c00750
110. Lohard S, Bourgeois N, Maillet L, Gautier F, Fétiveau A, Lasla H, et al. STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment. Nat Commun. (2020) 11:259. doi: 10.1038/s41467-019-13689-y
111. Kaneta A, Nakajima S, Okayama H, Matsumoto T, Saito K, Kikuchi T, et al. Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer. Cancer Immunol Immunother. (2022) 71:2765–76. doi: 10.1007/s00262-022-03200-w
112. Nakajima S, Kaneta A, Okayama H, Saito K, Kikuchi T, Endo E, et al. The impact of tumor cell-intrinsic expression of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) on the infiltration of CD8+ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable colorectal cancer. Cancers. (2023) 15:2826. doi: 10.3390/cancers15102826
113. Nassour J, Radford R, Correia A, Fusté JM, Schoell B, Jauch A, et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature. (2019) 565:659–63. doi: 10.1038/s41586-019-0885-0
114. Diamond JM, Vanpouille-Box C, Spada S, Rudqvist N-P, Chapman JR, Ueberheide BM, et al. Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs. Cancer Immunol Res. (2018) 6:910–20. doi: 10.1158/2326-6066.CIR-17-0581
115. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. (2015) 161:1046–57. doi: 10.1016/j.cell.2015.04.042
116. Robbins PD and Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. (2014) 14:195–208. doi: 10.1038/nri3622
117. Armstrong JPK, Holme MN, and Stevens MM. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano. (2017) 11:69–83. doi: 10.1021/acsnano.6b07607
118. An Y, Zhu J, Xie Q, Feng J, Gong Y, Fan Q, et al. Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling. Advanced Sci. (2024) 11:2308131. doi: 10.1002/advs.202308131
119. Wang B, Yu W, Jiang H, Meng X, Tang D, and Liu D. Clinical applications of STING agonists in cancer immunotherapy: current progress and future prospects. Front Immunol. (2024) 15:1485546. doi: 10.3389/fimmu.2024.1485546
120. Jang SC, Economides KD, Moniz RJ, Sia CL, Lewis N, McCoy C, et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun Biol. (2021) 4:497. doi: 10.1038/s42003-021-02004-5
121. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. (2017) 390:2769–78. doi: 10.1016/S0140-6736(17)32448-0
122. Murray A, Nguyen TM, Parker CE, Feagan BG, and MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Systematic Rev. (2020) 2020:CD000543. doi: 10.1002/14651858.CD000543.pub5
123. Chhaya V, Saxena S, Cecil E, Subramanian V, Curcin V, Majeed A, et al. Steroid dependency and trends in prescribing for inflammatory bowel disease – a 20-year national population-based study. Aliment Pharmacol Ther. (2016) 44:482–94. doi: 10.1111/apt.13700
124. Selinger CP, Parkes GC, Bassi A, Fogden E, Hayee B, Limdi JK, et al. A multi-centre audit of excess steroid use in 1176 patients with inflammatory bowel disease. Aliment Pharmacol Ther. (2017) 46:964–73. doi: 10.1111/apt.14334
125. D’Haens G. Systematic review: second-generation vs. conventional corticosteroids for induction of remission in ulcerative colitis. Aliment Pharmacol Ther. (2016) 44:1018–29. doi: 10.1111/apt.13803
126. Lichtenstein GR, Abreu MT, Cohen R, and Tremaine W. American gastroenterological association institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. (2006) 130:940–87. doi: 10.1053/j.gastro.2006.01.048
127. Pugliese D, Aratari A, Festa S, Ferraro PM, Monterubbianesi R, Guidi L, et al. Sustained clinical efficacy and mucosal healing of thiopurine maintenance treatment in ulcerative colitis: A real-life study. Gastroenterol Res Pract. (2018) 2018:1–7. doi: 10.1155/2018/4195968
128. Yamada S, Yoshino T, Matsuura M, Kimura M, Koshikawa Y, Minami N, et al. Efficacy and safety of long-term thiopurine maintenance treatment in Japanese patients with ulcerative colitis. Intest Res. (2015) 13:250. doi: 10.5217/ir.2015.13.3.250
129. Cai Z, Wang S, and Li J. Treatment of inflammatory bowel disease: A comprehensive review. Front Med. (2021) 8:765474. doi: 10.3389/fmed.2021.765474
130. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. (2019) 68:s1–s106. doi: 10.1136/gutjnl-2019-318484
131. Naganuma M, Yokoyama Y, Motoya S, Watanabe K, Sawada K, Hirai F, et al. Efficacy of apheresis as maintenance therapy for patients with ulcerative colitis in an open-label prospective multicenter randomised controlled trial. J Gastroenterol. (2020) 55:390–400. doi: 10.1007/s00535-019-01651-0
132. Ocansey DKW, Wang L, Wang J, Yan Y, Qian H, Zhang X, et al. Mesenchymal stem cell–gut microbiota interaction in the repair of inflammatory bowel disease: an enhanced therapeutic effect. Clin Trans Med. (2019) 8:e31. doi: 10.1186/s40169-019-0251-8
133. Mishra R, Dhawan P, Srivastava AS, and Singh AB. Inflammatory bowel disease: Therapeutic limitations and prospective of the stem cell therapy. WJSC. (2020) 12:1050–66. doi: 10.4252/wjsc.v12.i10.1050
134. Mao F, Wu Y, Tang X, Kang J, Zhang B, Yan Y, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve inflammatory bowel disease in mice. BioMed Res Int. (2017) 2017:1–12. doi: 10.1155/2017/5356760
135. Saeed RF, Awan UA, Saeed S, Mumtaz S, Akhtar N, and Aslam S. Targeted therapy and personalized medicine. In: Qazi AS and Tariq K, editors. Therapeutic approaches in cancer treatment. Cancer treatment and research. Springer International Publishing, Cham (2023). p. 177–205. doi: 10.1007/978-3-031-27156-4_10
136. Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, et al. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol. (2021) 14:156. doi: 10.1186/s13045-021-01164-5
137. Ma C, Yang D, Wang B, Wu C, Wu Y, Li S, et al. Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation. Sci Adv. (2020) 6:eaaz6717. doi: 10.1126/sciadv.aaz6717
138. Guilbaud L, Chen C, Domingues I, Kavungere EK, Marotti V, Yagoubi H, et al. Oral lipid-based nanomedicine for the inhibition of the cGAS-STING pathway in inflammatory bowel disease treatment. Mol Pharmaceutics. (2025) 22:2108–21. doi: 10.1021/acs.molpharmaceut.4c01297
139. Hoong BYD, Gan YH, Liu H, and Chen ES. cGAS-STING pathway in oncogenesis and cancer therapeutics. Oncotarget. (2020) 11:2930–55. doi: 10.18632/oncotarget.27673
140. Zhu X, Huang K, Kao X, Tang Z, Guo W, Wu T, et al. Death domain-associated protein (Daxx) impairs colon cancer chemotherapy by inhibiting the cGAS-STING pathway. OR. (2025) 33:1149–59. doi: 10.32604/or.2024.054930
141. Li M, Xiao J, Song S, Han F, Liu H, Lin Y, et al. PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer. BMC Med. (2024) 22:154. doi: 10.1186/s12916-024-03375-2
142. Duan J, Chen T, Li Q, Zhang Y, Lu T, Xue J, et al. Protein arginine methyltransferase 6 enhances immune checkpoint blockade efficacy via the STING pathway in MMR-proficient colorectal cancer. J Immunother Cancer. (2025) 13:e010639. doi: 10.1136/jitc-2024-010639
143. Luo B, Zhang S, Yu X, Tan D, Wang Y, and Wang M. Gasdermin E benefits CD8+T cell mediated anti-immunity through mitochondrial damage to activate cGAS-STING-interferonβ axis in colorectal cancer. biomark Res. (2024) 12:59. doi: 10.1186/s40364-024-00606-9
144. Wu X, Xu L, Li X, Zhou Y, Han X, Zhang W, et al. A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive colon cancer by triggering the cGAS-STING pathway. Cell Death Dis. (2023) 14:550. doi: 10.1038/s41419-023-06073-8
145. Liu C, Wang X, Qin W, Tu J, Li C, Zhao W, et al. Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer. Cancer Commun. (2023) 43:435–54. doi: 10.1002/cac2.12412
146. Huang X, Liang N, Zhang F, Lin W, and Ma W. Lovastatin-Induced Mitochondrial Oxidative Stress Leads to the Release of mtDNA to Promote Apoptosis by Activating cGAS-STING Pathway in Human Colorectal Cancer Cells. Antioxidants. (2024) 13:679. doi: 10.3390/antiox13060679
147. Yu X, Cai L, Yao J, Li C, and Wang X. Agonists and inhibitors of the cGAS-STING pathway. Molecules. (2024) 29:3121. doi: 10.3390/molecules29133121
148. Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, et al. Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay. PloS One. (2017) 12:e0184843. doi: 10.1371/journal.pone.0184843
149. Dai J, Huang Y-J, He X, Zhao M, Wang X, Liu Z-S, et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell. (2019) 176:1447–1460.e14. doi: 10.1016/j.cell.2019.01.016
150. Lama L, Adura C, Xie W, Tomita D, Kamei T, Kuryavyi V, et al. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. Nat Commun. (2019) 10:2261. doi: 10.1038/s41467-019-08620-4
151. An J, Woodward JJ, Sasaki T, Minie M, and Elkon KB. Cutting edge: antimalarial drugs inhibit IFN-β Production through blockade of cyclic GMP-AMP synthase–DNA interaction. J Immunol. (2015) 194:4089–93. doi: 10.4049/jimmunol.1402793
152. Wang M, Sooreshjani MA, Mikek C, Opoku-Temeng C, and Sintim HO. Suramin Potently Inhibits cGAMP Synthase, cGAS, in THP1 Cells to Modulate IFN-β Levels. Future Med Chem. (2018) 10:1301–17. doi: 10.4155/fmc-2017-0322
153. Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, et al. Targeting STING with covalent small-molecule inhibitors. Nature. (2018) 559:269–73. doi: 10.1038/s41586-018-0287-8
154. Li S, Hong Z, Wang Z, Li F, Mei J, Huang L, et al. The cyclopeptide astin C specifically inhibits the innate immune CDN sensor STING. Cell Rep. (2018) 25:3405–3421.e7. doi: 10.1016/j.celrep.2018.11.097
155. Xue L, Liu R, Zhang L, Qiu T, Liu L, Yin R, et al. Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING. Eur J Medicinal Chem. (2024) 279:116883. doi: 10.1016/j.ejmech.2024.116883
156. Hansen AL, Buchan GJ, Rühl M, Mukai K, Salvatore SR, Ogawa E, et al. Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling. Proc Natl Acad Sci USA. (2018) 115:E7768–75. doi: 10.1073/pnas.1806239115
157. Gogoi H, Mansouri S, and Jin L. The age of cyclic dinucleotide vaccine adjuvants. Vaccines. (2020) 8:453. doi: 10.3390/vaccines8030453
158. Chang W, Altman MD, Lesburg CA, Perera SA, Piesvaux JA, Schroeder GK, et al. Discovery of MK-1454: A potent cyclic dinucleotide stimulator of interferon genes agonist for the treatment of cancer. J Med Chem. (2022) 65:5675–89. doi: 10.1021/acs.jmedchem.1c02197
159. Kim D, Endo A, Fang FG, Huang K, Bao X, Choi H, et al. E7766, a macrocycle-bridged stimulator of interferon genes (STING) agonist with potent pan-genotypic activity. ChemMedChem. (2021) 16:1741–4. doi: 10.1002/cmdc.202100068
160. Chin EN, Yu C, Vartabedian VF, Jia Y, Kumar M, Gamo AM, et al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science. (2020) 369:993–9. doi: 10.1126/science.abb4255
161. Pan B-S, Perera SA, Piesvaux JA, Presland JP, Schroeder GK, Cumming JN, et al. An orally available non-nucleotide STING agonist with antitumor activity. Science. (2020) 369:eaba6098. doi: 10.1126/science.aba6098
162. Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang S-Y, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature. (2018) 564:439–43. doi: 10.1038/s41586-018-0705-y
163. Ohkuri T, Kosaka A, Ishibashi K, Kumai T, Hirata Y, Ohara K, et al. Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site. Cancer Immunol Immunother. (2017) 66:705–16. doi: 10.1007/s00262-017-1975-1
164. Zolg DP, Wilhelm M, Schnatbaum K, Zerweck J, Knaute T, Delanghe B, et al. Building ProteomeTools based on a complete synthetic human proteome. Nat Methods. (2017) 14:259–62. doi: 10.1038/nmeth.4153
165. Cai L, Wang Y, Chen Y, Chen H, Yang T, Zhang S, et al. Manganese( ii ) complexes stimulate antitumor immunity via aggravating DNA damage and activating the cGAS-STING pathway. Chem Sci. (2023) 14:4375–89. doi: 10.1039/D2SC06036A
166. Zhang Y, Li M, Li L, Qian G, Wang Y, Chen Z, et al. β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion. Nat Commun. (2020) 11:6000. doi: 10.1038/s41467-020-19849-9
167. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. (2015) 11:1018–30. doi: 10.1016/j.celrep.2015.04.031
168. Li T, Cheng H, Yuan H, Xu Q, Shu C, Zhang Y, et al. Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response. Sci Rep. (2016) 6:19049. doi: 10.1038/srep19049
169. Yuan L, Kulkarni M, Chiswick E, Koh C, Sandy P, Nabhan S, et al. A novel approach for first-in-human dose selection using population dose–response modelling to find a minimum anticipated biological effect level. Br J Clin Pharmacol. (2025) 91:2555–66. doi: 10.1002/bcp.70067
170. Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, Lemmens E, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. (2015) 7:283ra52–283ra52. doi: 10.1126/scitranslmed.aaa4306
171. Song J, Yang R, Chang J, Liu Y, Lu C, Chen L, et al. Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease. Acta Pharmacol Sin. (2023) 44:791–800. doi: 10.1038/s41401-022-01002-5
172. Gao F, Deng S, Liu Y, Wu P, Huang L, Zhu F, et al. Compound sophora decoction alleviates ulcerative colitis by regulating macrophage polarization through cGAS inhibition: network pharmacology and experimental validation. Aging (Albany NY). (2024) 16:6921–36. doi: 10.18632/aging.205734
173. Gao F, Zhu F, Shuai B, Wu M, Wei C, Yuan Y, et al. Quercetin ameliorates ulcerative colitis by restoring the balance of M2/M1 and repairing the intestinal barrier via downregulating cGAS–STING pathway. Front Pharmacol. (2024) 15:1351538. doi: 10.3389/fphar.2024.1351538
174. Du J, Fan Y, Fu J, Ge F, Zhu H, Yang S, et al. Deubiquitinating enzyme JOSD2 modulates cGAS to facilitate immune evasion in colorectal cancer. Oncoimmunology. (2025) 14:2590245. doi: 10.1080/2162402X.2025.2590245
175. Wu J, Li B, Chen Y, Zhang M, Li J, Dou G, et al. Andrographolide potentiates anti-tumor immunity in colorectal cancer (CRC) by targeting voltage-dependent anion channel (VDAC) and activating the cGAS-STING axis. J Gastrointest Oncol. (2025) 16:1550–61. doi: 10.21037/jgo-2025-592
176. Zhang X, Tian H, Chen Y, Liang B, Nice EC, Huang C, et al. A metal-organic nanoframework for efficient colorectal cancer immunotherapy by the cGAS-STING pathway activation and immune checkpoint blockade. J Nanobiotechnology. (2024) 22:592. doi: 10.1186/s12951-024-02836-3
177. Lan J, Deng Z, Wang Q, Li D, Fan K, Chang J, et al. Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway. Int J Biol Sci. (2024) 20:2507–31. doi: 10.7150/ijbs.94548
178. Liu C, Tang L, Yang W, Gu Y, Xu W, Liang Z, et al. cGAS/STING pathway and gastrointestinal cancer: Mechanisms and diagnostic and therapeutic targets (Review). Oncol Rep. (2024) 53:15. doi: 10.3892/or.2024.8848
179. Li Q, Wu P, Du Q, Hanif U, Hu H, and Li K. cGAS–STING, an important signaling pathway in diseases and their therapy. MedComm. (2024) 5:e511. doi: 10.1002/mco2.511
Keywords: CGAS, colorectal cancer, inflammatory bowel disease, STING, therapy
Citation: Chen X, Tang X, Chen S, Ye Y and Mao F (2026) cGAS-STING signaling: a therapeutic target in inflammatory bowel disease and related colorectal cancer. Front. Immunol. 16:1709908. doi: 10.3389/fimmu.2025.1709908
Received: 26 September 2025; Accepted: 24 December 2025; Revised: 19 December 2025;
Published: 15 January 2026.
Edited by:
Steven O'Reilly, Consultant, Sunderland, United KingdomReviewed by:
Milad khorasani, Neyshabur University of Medical Sciences, IranValerie Quesniaux, UMR7355 Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), France
Copyright © 2026 Chen, Tang, Chen, Ye and Mao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Fei Mao, bWFvZmVpMjAwM0B1anMuZWR1LmNu
†These authors have contributed equally to this work