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The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer Open
The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS–STING pathway was discovered as an important DNA-sensing mach…
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Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy Open
CD8 + T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumo…
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Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer Open
Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and c…
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PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer Open
Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor–indu…
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Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage Open
DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involv…
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STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 Open
Mountainous evidence suggests that inflammation, cardiomyocyte apoptosis and pyroptosis are involved in the development of sepsis and sepsis-induced cardiomyopathy (SIC). Stimulator of interferon genes (STING) is an indispensable molecule …
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STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity Open
Significance Tumor recognition by the immune system can occur spontaneously but has usually little impact on tumor growth. However, the cellular and molecular mechanisms that drive these responses could be exploited therapeutically to gene…
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PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness Open
PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads…
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Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis Open
Stimulator of interferon genes (STING) has been shown to be critical for controlling antiviral responses as well as anti-tumor adaptive immunity, but little is known regarding its regulation in human tumors. Here, we report that STING sign…
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Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury Open
Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate …
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Signalling strength determines proapoptotic functions of STING Open
Mammalian cells use cytosolic nucleic acid receptors to detect pathogens and other stress signals. In innate immune cells the presence of cytosolic DNA is sensed by the cGAS–STING signalling pathway, which initiates a gene expression progr…
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TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections Open
Significance The cGAS-STING pathway is important for immune defense against infection and cancer. STING activation triggers multiple signaling cascades leading to activation of IRF3, NF-κB, and autophagy. By generating mice harboring mutat…
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The host STING pathway at the interface of cancer and immunity Open
A major subset of human cancers shows evidence for spontaneous adaptive immunity, which is reflected by the presence of infiltrating CD8+ T cells specific for tumor antigens within the tumor microenvironment. This observation has raised th…
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Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer Open
We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed …
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NAD <sup>+</sup> supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS–STING Open
Significance Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of Alzheimer's disease (AD), but their interplay is not clear. AD mouse brains showed lower nicotinamide adenine dinucleoti…
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Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity Open
Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is …
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STING: a master regulator in the cancer-immunity cycle Open
The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Rece…
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Sensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS Open
Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here w…
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Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis Open
The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumo…
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STING Agonists as Cancer Therapeutics Open
The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pr…
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Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling Open
Most studies focus on how intestinal microbiota influence cancer immunotherapy through activating gut immunity. However, immunotherapies related to innate responses such as CD47 blockade rely on the rapid immune responses within the tumor …
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Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death Open
Stimulator of interferon genes (STING) was initially described as a sensor of intracellular bacterial and viral DNA and a promising adjuvant target in innate immune cells; more recently STING has also been shown to detect endogenous DNA an…
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The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum Open
Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and auto…
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Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses Open
Significance Kaposi’s sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. The cGMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is able to detect KSHV during primary …
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Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells Open
Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. He…
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STING pathway agonism as a cancer therapeutic Open
The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be dr…
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STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation Open
Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN-I. STING incites spontaneous immunity during immunogenic tumor growth and acc…
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STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death Open
STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by a…
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STING–IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity Open
Objective— Metabolic stress in obesity induces endothelial inflammation and activation, which initiates adipose tissue inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms underlying endothelial inflammati…
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Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes Open
Activation of the cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is critical for IFN and inflammatory gene expression during innate immune responses. However, the role of STING in adaptive immunity is still unknown…