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Apoptosis can feed back to regulate the cGAS-STING pathway. (1) Apoptosis can suppress the cGAS-STING pathway through the activation of caspases including caspase-3 and caspase-8. (2) Apoptosis can promote the cGAS-STING pathway through the release of mtDNA.
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The cGAS–STING signaling axis can be activated by cytosolic DNA, including both non-self DNA and self DNA. This axis is used by the innate immune system to monitor invading pathogens and/or damage. Increasing evidence has suggested that the cGAS-STING pathway not only facilitates inflammatory responses and the production of type I interferons (IFN)...
Contexts in source publication
Context 1
... cGAS-STING pathway can be inhibited by caspase-3 ( Figure 2). Indeed, cGAS can be cleaved by apoptotic caspase-3 at position D319 during viral infection [15]. ...
Context 2
... mutants DD121/125AA and DDD116/121/125AAA were completely resistant to ABT263 (Navitoclax), a Bcl-2 inhibitor, treatment-caused IRF3 cleavage [15]. Furthermore, the cGAS-STING pathway can be inhibited by caspase-8 (Figure 2). A study in Bombyx mori has shown that a caspase-8-like protein (Casp8L) was able to suppress the STING-mediated antiviral pathway [63]. ...
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... mtDNA leaks from damaged mitochondria into the cytosol, it can serve as a type of mitochondrial danger-associated molecular pattern (mtDAMP) and can engage various PRRs. The recognition of mtDAMPs by PRRs leads to the activation of the innate immune response (Figure 2). During apoptosis, mtDNA release is mediated by macro-pores in the mitochondrial outer membrane created by the oligomerization of the proteins Bax and Bak [66]. ...
Citations
... Unbiased gene set enrichment analysis (GSEA) of the most significantly downregulated genes in SMARCA4 knockout tumors showed interferon alpha (IFNa) and interferon gamma (IFNg) pathways as top enriched pathways (Fig. 3C-E). IFNa belong to type I IFN family which is downstream of cGAS-STING pathway (48)(49)(50)(51). The cGAS-STING pathway has emerged as the master mediator of inflammation in the settings of stress, tissue damage, infection and cancer by sensing microbial and host derived DNAs (collectively known as danger-associated molecules-DAMPs) and is an attractive therapeutic target (which was not certified by peer review) is the author/funder. ...
Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, we show that SMARCA4 loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME) . Mechanistically, we show that SMARCA4 loss in tumor cells led to profound downregulation of STING, IL1β and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as STING, IL1β, type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated with STING and IL1β, indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response of SMARCA4-mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.
... When heterologous DNA detected, the cGAS will activate the synthetic of a second signal molecule called cyclic GMP-AMP (cGAMP), and then activate the STING [45][46][47]. Recent discoveries have unveiled the involvement of the cGAS-STING pathway in DNA damage repair, nuclear factor kappa-B (NF-κB) related inflammatory responses and autolysosome-dependent cell death [48][49][50]. Existing literature indicates that in macrophages and human peripheral blood mononuclear cells, activated STING engages with NCOA4, initiating a process of STING-driven cytophagy targeting ferritins and ultimately inducing ferroptosis [51]. Our previous research has confirmed that during cerebral ischemia-reperfusion, the cGAS-STING pathway can regulate excessive activation of NCOA4-mediated ferritinophagy, exacerbating brain damage in mice [19]. ...
Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (P < 0.05). This activation contributed to oxidative stress (P < 0.05), enhanced autophagy (P < 0.05) and cell death (P < 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (P < 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (P < 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (P < 0.05), oxidative stress (P < 0.05), and cell damage (P < 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (P < 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (P < 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (P < 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.
... extracellular) threats, such as various pathogens, as well as endogenous (i.e. intracellular) alterations indicative of cellular dysfunction or imminent risk [26][27][28]. While cancer cells are not strictly defined as pathogens due to their endogenous origin, they exhibit molecular features distinct from healthy cells that activate damage-related pathways such as STING. ...
... This illustrates the importance of this topic and the rising attention among academics transformed cells during carcinogenesis. Thus, by sensing abnormal intracellular conditions, the STING pathway represents a conserved innate immune strategy that safeguards genomic integrity and homeostasis against diverse threats, whether originating from outside or developing within the body [26,27,29,30]. The STING signaling cascade is initiated upon detection of cytosolic DNA, which can be derived from invading viruses or, in cancer cells, genomic DNA that has leaked into the cytosol from the nucleus. ...
The stimulator of the interferon genes (STING) signaling pathway plays a crucial role in innate immunity by detecting cytoplasmic DNA and initiating antiviral host defense mechanisms. The STING cascade is triggered when the enzyme cyclic GMP-AMP synthase (cGAS) binds cytosolic DNA and synthesizes the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum adaptor STING, leading to the activation of kinases TBK1 and IRF3 that induce interferon production. Secreted interferons establish an antiviral state in infected and adjacent cells. Beyond infections, aberrant DNA in cancer cells can also activate the STING pathway. Preclinical studies have shown that pharmacological STING agonists like cyclic dinucleotides elicit antitumor immunity when administered intratumorally by provoking innate and adaptive immunity. Combining STING agonists with immune checkpoint inhibitors may improve outcomes by overcoming tumor immunosuppression. First-generation STING agonists encountered challenges like poor pharmacokinetics, limited tumor specificity, and systemic toxicity. The development of the next-generation STING-targeted drugs to realize the full potential of engaging this pathway for cancer treatment can be a solution to overcome the current challenges, but further studies are required to determine optimal applications and combination regimens for the clinic. Notably, the controlled activation of STING is needed to preclude adverse effects. This review explores the mechanisms and effects of STING activation, its role in cancer immunotherapy, and current challenges.
... Recent studies also provide interesting clues regarding the role of the Cyclic GMP-AMP synthase (cGAS) in the regulation of cell death subsequent to oxidative stress. Beside its now well documented role in the innate immune response, cGAS also acts in the nucleus as a chromatinbound protein that inhibits reparation of double-strand DNA breaks by homologous recombination (HR), thereby accelerating genome destabilization, micronucleus generation, and cell death under conditions of genomic stress, such as oxidative stress [74][75][76]. This function of cGAS appears to be independent of the stimulator of interferon genes (STING) adaptor, which is critical to mediate the innate immune function of cGAS. ...
... The innate immune system is the main contributor of the host defense against pathogen invasion and tissue damage (1). Pattern recognition receptors (PRRs) on innate immune cells recognize the pathogen-associated molecular patterns (PAMPs) carried by invading pathogens and the endogenous damage-associated molecular patterns (DAMPs) released by damaged cells, and then activates the innate immune response and prevents body damage (2,3). ...
As a canonical cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) plays a key role in innate immunity. In recent years, a growing number of studies have shown that cGAS can also be located in the nucleus and plays new functions such as regulating DNA damage repair, nuclear membrane repair, chromosome fusion, DNA replication, angiogenesis and other non-canonical functions. Meanwhile, the mechanisms underlying the nucleo-cytoplasmic transport and the regulation of cGAS activation have been revealed in recent years. Based on the current understanding of the structure, subcellular localization and canonical functions of cGAS, this review focuses on summarizing the mechanisms underlying nucleo-cytoplasmic transport, activity regulation and non-canonical functions of cGAS in the nucleus. We aim to provide insights into exploring the new functions of cGAS in the nucleus and advance its clinical translation.
... Furthermore, elevated baseline cGAS expression significantly correlated with treatment response in patients receiving microtubule-targeting agents in combination with immune CPI (67)(68)(69). Carboplatin, a second-generation platinum antitumor drug derived from cisplatin, was also recently shown to suppress human melanoma through the activation of cGAS/STING pathway-mediated apoptosis, an effect facilitated through the upregulation of TREX-1 expression in human melanoma (70,71). It is known that chemotherapy-triggered DNA damage events can activate the cGAS/STING pathway (72). ...
The anticancer efficacy of Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate internalized through a sortilin-mediated process, was assessed in a triple-negative breast cancer-derived MDA-MB-231 immunocompromised xenograft tumor model where complete tumor regression was observed for more than 40 days after the last treatment. Surprisingly, immunohistochemistry analysis revealed high staining of STING, a master regulator in the cancer-immunity cycle. A weekly administration of TH1902 as a single agent in a murine B16-F10 melanoma syngeneic tumor model demonstrated superior tumor growth inhibition than did docetaxel. A net increase in CD45 leukocyte infiltration within TH1902-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages was observed. Increased staining of perforin, granzyme B, and caspase-3 was suggestive of elevated cytotoxic T and natural killer cell activities. Combined TH1902/anti-PD-L1 treatment led to increases in tumor growth inhibition and median animal survival. TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes.
... The presence of naked DNA in the cytoplasm of mammalian cells triggers a cellular response initiated by the DNA sensing pathway. Recently, cyclic GMP-AMP synthase (cGAS) was characterized as a primary cytosolic DNA sensor that triggers type I interferons (IFNs) and inflammatory cytokines upon binding dsDNA [2,3]. cGAS can be activated by dsDNA in a length-dependent but sequence-independent manner by binding the DNA phosphate backbone [4]. ...
... DNase II is localized in the lysosomes and is largely responsible for the clearance of DNA. 3 Self-DNA in cytoplasm is degraded by TREX1. TREX1, localized in the cytosol, is a powerful DNA-degrading enzyme. ...
cGAS is a cytosolic DNA sensor that activates innate immune responses by producing the second messenger 2′3′-cGAMP, which activates the adaptor STING. cGAS senses dsDNA in a length-dependent but sequence-independent manner, meaning it cannot discriminate self-DNA from foreign DNA. In normal physiological conditions, cellular DNA is sequestered in the nucleus by a nuclear envelope and in mitochondria by a mitochondrial membrane. When self-DNA leaks into the cytosol during cellular stress or mitosis, the cGAS can be exposed to self-DNA and activated. Recently, many studies have investigated how cGAS keeps inactive and avoids being aberrantly activated by self-DNA. Thus, this narrative review aims to summarize the mechanisms by which cGAS avoids sensing self-DNA under normal physiological conditions.
... Additionally, our results suggested the specific functions of STING induced by SAMHD1 deficiency. It was well known that STING was associated with cell death regulation and cytokine production [53][54][55]. Necroptosis, caspase-dependent apoptosis, and pyroptosis were mediated by STING in SAMHD1-deficient DLBCL cells. Caspase activation led to cGAS and IRF3 cleavage, further inhibiting cGAS expression and IFN secretion [56]. ...
Genomic instability is a significant driver of cancer. As the sensor of cytosolic DNA, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in regulating anti-tumor immunity and cell death. However, the role and regulatory mechanisms of STING in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we reported that sterile alpha motif and HD domain-containing protein 1 (SAMHD1) deficiency induced STING expression and inhibited tumor growth in DLBCL. High level of SAMHD1 was associated with poor prognosis in DLBCL patients. Down-regulation of SAMHD1 inhibited DLBCL cell proliferation both in vitro and in vivo. Moreover, we found that SAMHD1 deficiency induced DNA damage and promoted the expression of DNA damage adaptor STING. STING overexpression promoted the formation of Caspase 8/RIPK3/ASC, further leading to MLKL phosphorylation, Caspase 3 cleavage, and GSDME cleavage. Up-regulation of necroptotic, apoptotic, and pyroptotic effectors indicated STING-mediated PANoptosis. Finally, we demonstrated that the STING agonist, DMXAA, enhanced the efficacy of a PD-L1 inhibitor in DLBCL. Our findings highlight the important role of STING-mediated PANoptosis in restricting DLBCL progression and provide a potential strategy for enhancing the efficacy of immune checkpoint inhibitor agents in DLBCL.
... The ability of cGAS/STING signaling to activate the NLRP3 inflammasome is well documented and seems to involve both upregulation of NLRP3 pathway mediators as well as the induction of potassium efflux that triggers inflammasome assembly. [31][32][33] This is consistent with our findings of correlation between cGAS/STING activation and NLRP3 expression in the CRC cells in addition to the increase in ASC specks we identified upon dual stimulation. In contrast, the mechanism by which NLRP3 enhances cGAS/STING signaling is not yet clear and contradicts several previous studies that have found NLRP3 activation to repress cGAS/STING signaling. ...
... 33,[41][42][43] In addition, NLRP3mediated cGAS/STING activation could result from its role as a stress sensor, especially in MSI CRCs that experience high levels of genotoxic or ER stress induced by excessive point mutations and aberrant proteins. 32,44 Alternatively, NLRP3 could be activated by signaling from the high levels of immune cells that infiltrate MSI CRCs or by specific microbial taxa that have been found to be enriched in MSI CRCs. [45][46][47][48] . ...
Colorectal cancer (CRC) is a highly prevalent and deadly disease that is largely refractory to immunotherapy. The only CRC subset that responds to these therapies is characterized by prevalent microsatellite instability (MSI), extensive CD8+ T cell infiltration and high expression of innate immune signaling pathways. Endogenous activation of the cGAS/STING pathway is essential for the CD8+ T cell antitumor response in MSI CRCs, suggesting that activating it in other CRCs could boost immunotherapy response rates. We show that cGAS/STING signaling can be enhanced by costimulation of the NLRP3 inflammasome and that dual stimulation increases CD8+ T cell-mediated antitumor immunity in both MSI and non-MSI CRCs. The ability of NLRP3 to boost cGAS/STING signaling was specific and did not occur with activation of other innate immune pathways such as AIM2 or TLRs. Cooperativity between cGAS/STING and NLRP3 proceeded via a positive feedback loop that was inflammasome-independent and required early crosstalk between the signaling mediators and regulation of their gene expression. Notably, increased cGAS/STING signaling enhanced CD8+ T cell activation when in conjunction with anti-PD1 immunotherapy, suggesting that signaling via NLRP3 could further boost this response and render otherwise resistant CRC susceptible to immunotherapy.
Significance
Innate immune signaling pathways cooperatively regulate CD8+ T cell-mediated antitumor immunity in both hot and cold tumors. In addition to serving as predictive biomarkers, these pathways can be therapeutically targeted to increase response rates to immunotherapy while minimizing undesirable adverse events.
... In addition to IRF3-and NF-κB-mediated gene transcriptions, STING also triggers cell autophagy and apoptosis [12,13]. Recent studies have shown that STING can cause canonical autophagy and non-canonical autophagy [12]. ...
... In addition, STING is also able to induce non-canonical autophagy by directly interacting with microtubule-associated protein light chain 3 (LC3) through its LC3 interacting regions (LIRs) [15], and the ER-Golgi intermediate compartment (ERGIC) is used as the membrane source of LC3 lipidation and autophagy formation [15][16][17]. Apoptosis, also known as the non-inflammatory type of programmed cell death, is one of the most widely studied cell death pathways [13,18]. The mechanism of STING inducing apoptosis is not clear, but most studies point to ER stress [19][20][21]. ...
... In this study, we first demonstrated the IFN-independent antiviral activity of chSTING in both mammalian and chicken cells (Figures 1-3). It is known that STING can not only induce IFN, but also activate NF-κB, autophagy and apoptosis [12,13,32]. First, chSTING pLxVS sub S366A and chSTING ∆CTT have differential NF-κB signaling ( Figure 2C), but the antiviral activity of these two chSTING mutants are similar ( Figure 2F,G). ...
It has been recently recognized that the DNA sensing innate immune cGAS-STING pathway exerts an IFN-independent antiviral function; however, whether and how chicken STING (chSTING) exerts such an IFN-independent antiviral activity is still unknown. Here, we showed that chSTING exerts an antiviral activity in HEK293 cells and chicken cells, independent of IFN production. chSTING was able to trigger cell apoptosis and autophagy independently of IFN, and the apoptosis inhibitors, rather than autophagy inhibitors, could antagonize the antiviral function of chSTING, suggesting the involvement of apoptosis in IFN-independent antiviral function. In addition, chSTING lost its antiviral function in IRF7-knockout chicken macrophages, indicating that IRF7 is not only essential for the production of IFN, but also participates in the other activities of chSTING, such as the apoptosis. Collectively, our results showed that chSTING exerts an antiviral function independent of IFN, likely via apoptosis.
