Prolonged activation of innate immune pathways by a polyvalent STING agonist

Nat Biomed Eng. 2021 May;5(5):455-466. doi: 10.1038/s41551-020-00675-9. Epub 2021 Feb 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity, Innate*
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Membrane Proteins / agonists*
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Nucleotides, Cyclic / administration & dosage*
  • Nucleotides, Cyclic / pharmacology
  • Polymers / administration & dosage*
  • Polymers / pharmacology
  • THP-1 Cells


  • Membrane Proteins
  • Nucleotides, Cyclic
  • Polymers
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate

Associated data

  • figshare/10.6084/m9.figshare.13356464