Journal
NATURE BIOMEDICAL ENGINEERING
Volume 5, Issue 5, Pages 455-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41551-020-00675-9
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Funding
- National Institutes of Health [U54 CA244719]
- Mendelson-Young Endowment in Cancer Therapeutics
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A novel polyvalent STING agonist extends the activation of innate-immunity pathways through the formation of STING condensates and leads to synergistic therapeutic outcomes in vivo when combined with the STING ligand cGAMP.
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. A polyvalent STING agonist prolongs the activation of innate-immunity pathways through the formation of STING condensates, and leads to synergistic therapeutic outcomes in vivo when combined with the STING ligand cGAMP.
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