Roles of the cGAS-STING Pathway in Cancer Immunosurveillance and Immunotherapy

Yum, Seoyun; Li, Minghao; Frankel, Arthur E.; Chen, Zhijian J.

doi:10.1146/annurev-cancerbio-030518-055636

Cited by 82 publications

(80 citation statements)

References 139 publications

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“…Many therapeutic strategies targeting the cGAS-STING pathway have been developed and tested in preclinical models. 55 2′3′-cGAMP, the endogenous ligand of STING, reduced implanted tumor growth by activating and recruiting CD8 + T cells to the tumor microenvironment. 37 , 54 Combining cGAMP and immune checkpoint inhibitors induced a synergistic effect in controlling tumor growth, demonstrating that activation of STING can potentiate the effect of immune checkpoint inhibitors.…”

Section: The Role Of Cgas In Antitumor Immunitymentioning

confidence: 99%

Old dogs, new trick: classic cancer therapies activate cGAS

2020

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The discovery of cancer immune surveillance and immunotherapy has opened up a new era of cancer treatment. Immunotherapies modulate a patient’s immune system to specifically eliminate cancer cells; thus, it is considered a very different approach from classic cancer therapies that usually induce DNA damage to cause cell death in a cell-intrinsic manner. However, recent studies have revealed that classic cancer therapies such as radiotherapy and chemotherapy also elicit antitumor immunity, which plays an essential role in their therapeutic efficacy. The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and the downstream effector Stimulator of Interferon Genes (STING) have been determined to be critical for this interplay. Here, we review the antitumor roles of the cGAS-STING pathway during tumorigenesis, cancer immune surveillance, and cancer therapies. We also highlight classic cancer therapies that elicit antitumor immune responses through cGAS activation.

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Section: The Role Of Cgas In Antitumor Immunitymentioning

confidence: 99%

Old dogs, new trick: classic cancer therapies activate cGAS

2020

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“…Disrupting Site-C Interface Represents a Strategy for Crystallization of h-cGAS CD -DNA Complex. An important and challenging current goal has been to discover specific inhibitors of h-cGAS, given their potential as valuable therapeutics (39)(40)(41)(42)(43). Such structureguided rational drug design approaches have been undertaken to date on the apo h-cGAS CD (44,45) and the m-cGAS CD -DNA complexes (25), but have been hindered until recently (20), by the absence of a structure of the DNA-bound h-cGAS CD complex.…”

Section: Site-c Interface Promotes Dna Condensation Ability Of Cgas Asmentioning

confidence: 99%

Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation

Xie

Lama

Adura

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

144

107

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The cyclic GMP-AMP synthase (cGAS)-cGAMP-STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGAS CD -DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGAS CD -DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS-DNA interface. We also report the crystal structure of the h-cGAS CD -DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGAS CD , thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site-binding inhibitors.h-cGAS-DNA complex | DNA-binding cGAS mutations | multivalent interactions | liquid-phase condensation

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“…A bulk of studies have exhaustively summarized the role of cGAS/STING pathway in regulating antipathogenic and antitumor responses and the adaptive changes of cancerous cells and pathogens to escape cGAS supervision [8,[81][82][83][84]. As we explore and know more about this pathway, we are able to find more in other aspects.…”

Section: Roles Of the Cgas/sting Pathway In Physiological Regulatory mentioning

confidence: 99%

cGAS/STING: novel perspectives of the classic pathway

Gao

Tang

et al. 2020

Mol Biomed

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Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and innate immune response initiator. Binding with exogenous or endogenous nucleic acids, cGAS activates its downstream adaptor, stimulator of interferon genes (STING). STING then triggers protective immune to enable the elimination of the pathogens and the clearance of cancerous cells. Apparently, aberrantly activated by self-DNA, cGAS/STING pathway is threatening to cause autoimmune and inflammatory diseases. The effects of cGAS/STING in defenses against infection and autoimmune diseases have been well studied, still it is worthwhile to discuss the roles of cGAS/STING pathway beyond the “classical” realm of innate immunity. Recent studies have revealed its involvement in non-canonical inflammasome formation, calcium hemostasis regulation, endoplasmic reticulum (ER) stress response, perception of leaking mitochondrial DNA (mtDNA), autophagy induction, cellular senescence and senescence-associated secretory phenotype (SASP) production, providing an exciting area for future exploration. Previous studies generally focused on the function of cGAS/STING pathway in cytoplasm and immune response. In this review, we summarize the latest research of this pathway on the regulation of other physiological process and STING independent reactions to DNA in micronuclei and nuclei. Together, these studies provide a new perspective of cGAS/STING pathway in human diseases.

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Roles of the cGAS-STING Pathway in Cancer Immunosurveillance and Immunotherapy

Cited by 82 publications

References 139 publications

Old dogs, new trick: classic cancer therapies activate cGAS

Old dogs, new trick: classic cancer therapies activate cGAS

Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation

cGAS/STING: novel perspectives of the classic pathway

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