Prolonged activation of innate immune pathways by a polyvalent STING agonist
Open Access
- 8 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Biomedical Engineering
- Vol. 5 (5), 455-466
- https://doi.org/10.1038/s41551-020-00675-9
Abstract
The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. Here, we show that a polyvalent STING agonist—a pH-sensitive polymer bearing a seven-membered ring with a tertiary amine (PC7A)—activates innate-immunity pathways through the polymer-induced formation of STING–PC7A condensates. In contrast to the natural STING ligand 2′,3′-cyclic-GMP-AMP (cGAMP), PC7A stimulates the prolonged production of pro-inflammatory cytokines by binding to a non-competitive STING surface site that is distinct from the cGAMP binding pocket. PC7A induces antitumour responses that are dependent on STING expression and CD8+ T-cell activity, and the combination of PC7A and cGAMP led to synergistic therapeutic outcomes (including the activation of cGAMP-resistant STING variants) in mice bearing subcutaneous tumours and in resected human tumours and lymph nodes. The activation of the STING pathway through polymer-induced STING condensation may offer new therapeutic opportunities.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | Center for Information Technology (U54 CA244719)
- U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719, U54 CA244719)
- U.S. Department of Health & Human Services | National Institutes of Health (U54 CA244719)
This publication has 57 references indexed in Scilit:
- Roles of the cGAS-STING Pathway in Cancer Immunosurveillance and ImmunotherapyAnnual Review of Cancer Biology, 2019
- STING activation in cancer immunotherapyTheranostics, 2019
- Regulation and function of the cGAS–STING pathway of cytosolic DNA sensingNature Immunology, 2016
- STING: infection, inflammation and cancerNature Reviews Immunology, 2015
- Type I interferons in anticancer immunityNature Reviews Immunology, 2015
- STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic TumorsImmunity, 2014
- Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon PathwayScience, 2013
- Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNAScience, 2013
- STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunityNature, 2009
- Interferons, immunity and cancer immunoeditingNature Reviews Immunology, 2006