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Second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP): the cell autonomous and non-autonomous roles in cancer progression

Acta Pharmacologica Sinica volume 45, pages 890–899 (2024)Cite this article

Abstract

Cytosolic double-stranded DNA (dsDNA) is frequently accumulated in cancer cells due to chromosomal instability or exogenous stimulation. Cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, which is activated upon binding to dsDNA to synthesize the crucial second messenger 2’3’-cyclic GMP-AMP (2’3’-cGAMP) that in turn triggers stimulator of interferon genes (STING) signaling. The canonical role of cGAS-cGAMP-STING pathway is essential for innate immunity and viral defense. Recent emerging evidence indicates that 2’3’-cGAMP plays an important role in cancer progression via cell autonomous and non-autonomous mechanisms. Beyond its role as an intracellular messenger to activate STING signaling in tumor cells, 2’3’-cGAMP also serves as an immunotransmitter produced by cancer cells to modulate the functions of non-tumor cells especially immune cells in the tumor microenvironment by activating STING signaling. In this review, we summarize the synthesis, transmission, and degradation of 2’3’-cGAMP as well as the dual functions of 2’3’-cGAMP in a STING-dependent manner. Additionally, we discuss the potential therapeutic strategies that harness the cGAMP-mediated antitumor response for cancer therapy.

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Fig. 1: The multifaceted effects of cGAMP in tumor cells and tumor microenvironment.

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Acknowledgements

This work was supported by State Key Laboratory of Chemical Biology.

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Authors and Affiliations

  1. Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China

    Xiao-yu Ma, Man-man Chen & Ling-hua Meng

  2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China

    Xiao-yu Ma, Man-man Chen & Ling-hua Meng

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Xiao-yu Ma, Man-man Chen & Ling-hua Meng

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  1. Xiao-yu Ma
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Ma, Xy., Chen, Mm. & Meng, Lh. Second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP): the cell autonomous and non-autonomous roles in cancer progression. Acta Pharmacol Sin 45, 890–899 (2024). https://doi.org/10.1038/s41401-023-01210-7

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