Prolonged activation of innate immune pathways by a polyvalent STING agonist

Suxin Li, Min Luo, Zhaohui Wang, Qiang Feng, Jonathan Wilhelm, Xu Wang, Wei Li, Jian Wang, Agnieszka Cholka, Yang xin Fu, Baran D. Sumer, Hongtao Yu, Jinming Gao

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalNature Biomedical Engineering
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications

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