Therapeutic Development by Targeting the cGAS-STING Pathway in Autoimmune Disease and Cancer

Qiu-mei, LI; Tian, Shuoran; Liang, Jiadi; Fan, Jiqiang; Lai, Junzhong; Chen, Qi

doi:10.3389/fphar.2021.779425

Cited by 18 publications

(15 citation statements)

References 84 publications

(112 reference statements)

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“…There are many excellent summaries of the large amount of data that has become available about the experience with STING agonists in the clinics and beyond; these data will not be discussed in this review [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ].…”

Section: Sting Agonists In Cancermentioning

confidence: 99%

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

Guerini

2022

Cells

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The cGAS STING pathway has received much attention in recent years, and it has been recognized as an important component of the innate immune response. Since the discovery of STING and that of cGAS, many observations based on preclinical models suggest that the faulty regulation of this pathway is involved in many type I IFN autoinflammatory disorders. Evidence has been accumulating that cGAS/STING might play an important role in pathologies beyond classical immune diseases, as in, for example, cardiac failure. Human genetic mutations that result in the activation of STING or that affect the activity of cGAS have been demonstrated as the drivers of rare interferonopathies affecting young children and young adults. Nevertheless, no data is available in the clinics demonstrating the therapeutic benefit in modulating the cGAS/STING pathway. This is due to the lack of STING/cGAS-specific low molecular weight modulators that would be qualified for clinical exploration. The early hopes to learn from STING agonists, which have reached the clinics in recent years for selected oncology indications, have not yet materialized since the initial trials are progressing very slowly. In addition, transforming STING agonists into potent selective antagonists has turned out to be more challenging than expected. Nevertheless, there has been progress in identifying novel low molecular weight compounds, in some cases with unexpected mode of action, that might soon move to clinical trials. This study gives an overview of some of the potential indications that might profit from modulation of the cGAS/STING pathway and a short overview of the efforts in identifying STING modulators (agonists and antagonists) suitable for clinical research and describing their potential as a “drug”.

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Section: Sting Agonists In Cancermentioning

confidence: 99%

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

Guerini

2022

Cells

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“…[ 134 ] While cGAS was shown to be also a target of broad acting molecules, such as Aspirin and Suramin (reviewed in ref. [ 135 ] ) no specific cGAS inhibitor has entered clinical trials. In the future, efforts will need to be made to develop specific, potent and safe inhibitors of cGAS in order to fulfill this unmeet clinical need.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

et al. 2023

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The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.

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“…[99] In summary, the present study of mtDNA-cGAS-STING pathway regulators in the eld of nephrology mainly focuses on cGAS and STING inhibitors, as well as drugs affecting mitochondrial permeability. [100][101][102]…”

Section: Therapeutic Targeting Of the Mtdna-cgas-sting Signaling Path...mentioning

confidence: 99%

Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway

Li,

Liu,

Feng

et al. 2024

Chinese Medical Journal

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Over the past decade, mitochondrial dysfunction has been investigated as a key contributor to acute and chronic kidney disease. However, the precise molecular mechanisms linking mitochondrial damage to kidney disease remain elusive. The recent insights into the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthetase (cGAS)-stimulator of interferon gene (STING) signaling pathway have revealed its involvement in many renal diseases. One of these findings is that mitochondrial DNA (mtDNA) induces inflammatory responses via the cGAS-STING pathway. Herein, we provide an overview of the mechanisms underlying mtDNA release following mitochondrial damage, focusing specifically on the association between mtDNA release-activated cGAS-STING signaling and the development of kidney diseases. Furthermore, we summarize the latest findings of cGAS-STING signaling pathway in cell, with a particular emphasis on its downstream signaling related to kidney diseases. This review intends to enhance our understanding of the intricate relationship among the cGAS-STING pathway, kidney diseases, and mitochondrial dysfunction.

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Therapeutic Development by Targeting the cGAS-STING Pathway in Autoimmune Disease and Cancer

Cited by 18 publications

References 84 publications

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway

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