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.
Highlights
The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer
In this Article, we report that PC7A is a polyvalent STING agonist that acts through polymer-induced phase condensation of STING to activate an innate immune response with prolonged cytokine expression compared with cGAMP
To understand how PC7A-induced STING activation differs from cGAMP20,21, we first investigated the intracellular distribution of GFP-labelled STING and the downstream signals in live cells in response to treatment
Summary
The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. A previous study has shown that DNA-induced liquid phase separation of cGAS triggers innate immunity[32] By forming such biomolecular condensates, proteins involved in signalling cascades can be enriched in membraneless assemblies and amplify responses to small changes in the microenvironment. We previously synthesized a library of pH-sensitive polymers with linear or cyclic tertiary amine structures, among which a polymer with a cyclic seven-membered ring (PC7A) has shown a strong vaccine adjuvant effect through the STING-dependent pathway[17] In this Article, we report that PC7A is a polyvalent STING agonist that acts through polymer-induced phase condensation of STING to activate an innate immune response with prolonged cytokine expression compared with cGAMP. We provide a proof of principle for new cancer immunotherapy strategies targeting the STING pathway
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