The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Prolonged activation of innate immune pathways by a polyvalent STING agonist
Open accessAbstract
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.
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Cites
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Cited by
Sun, X., Zhang, Y., Li, J., Park, K. S., Han, K., Zhou, X., Xu, Y., Nam, J., Xu, J., Shi, X., et al. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00962-9 · Cited by 788
Cellular functions of cGAS-STING signaling
Chen, C., & Xu, P. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.11.001 · Cited by 451
Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy
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Metadata
- Authors
- Li, S., Luo, M., Wang, Z., Feng, Q., Wilhelm, J., Wang, X., Li, W., Wang, J., Cholka, A., Fu, Y.-X., Sumer, B. D., Yu, H., & Gao, J.
- Venue
- Nature Biomedical Engineering
- Published
- 2021-02-08
- Volume
- 5
- Issue
- 5
- Pages
- 455-466
- ISSN
- 2157-846X (ISSN-L)
- OpenAlex
- W3126746996
- Cited by
- 317
- References
- 10
- FWCI
- 14.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Li, S., Luo, M., Wang, Z., Feng, Q., Wilhelm, J., Wang, X., Li, W., Wang, J., Cholka, A., Fu, Y.-X., Sumer, B. D., Yu, H., & Gao, J. (2021). Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-020-00675-9
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