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The cGAS–STING pathway as a therapeutic target in inflammatory diseases

Nature Reviews Immunology volume 21, pages 548–569 (2021)Cite this article

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Abstract

The cGAS–STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage. Underlying this broad involvement of the cGAS–STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules. Insights into the structural and molecular biology of the cGAS–STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS–STING axis in a number of inflammatory diseases in humans. Here, we outline the principal elements of the cGAS–STING signalling cascade and discuss the general mechanisms underlying the association of cGAS–STING activity with various autoinflammatory, autoimmune and degenerative diseases. Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications.

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Fig. 1: Overview of the cGAS–STING signalling pathway.
Fig. 2: cGAS–STING effector mechanisms and intercellular cGAMP transmission.
Fig. 3: Mechanisms underlying cGAS–STING activity in sterile inflammatory conditions.
Fig. 4: Mechanisms of action of inhibitors targeting cGAS and STING.

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Acknowledgements

The authors thank W. R. Roush and H. M. Seidel for advice during the preparation of this document. A.A. acknowledges support from the SNF (31003A-159836) and the European Research Council (ERC-StG: 804933).

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Authors and Affiliations

  1. Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland

    Alexiane Decout & Andrea Ablasser

  2. IFM Therapeutics, Boston, MA, USA

    Jason D. Katz & Shankar Venkatraman

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  2. Jason D. Katz
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A.A. is a member of the scientific advisory board of IFM Therapeutics and scientific co-founder of IFM Due. J.D.K. and S.V. are employees of IFM Therapeutics. A.D. declares no competing interests.

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Decout, A., Katz, J.D., Venkatraman, S. et al. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 21, 548–569 (2021). https://doi.org/10.1038/s41577-021-00524-z

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