{"doi":"10.1038/s41551-020-00675-9","title":"Prolonged activation of innate immune pathways by a polyvalent STING agonist","abstract":"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.","journal":"Nature Biomedical Engineering","year":2021,"id":145798,"datarank":5.362761370518086,"base_score":5.736572297479192,"endowment":5.736572297479192,"self_citation_contribution":0.8604858446218789,"citation_network_contribution":4.5022755258962075,"self_endowment_contribution":0.8604858446218789,"citer_contribution":4.5022755258962075,"corpus_percentile":null,"corpus_rank":null,"citation_count":309,"citer_count":100,"citers_with_citation_signal":100,"citers_with_endowment":100,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.13356464"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":618864,"name":"Min Luo","orcid":"0000-0002-5276-9327","position":1,"is_corresponding":false},{"id":285063,"name":"Zhaohui Wang","orcid":"0000-0001-7994-7464","position":2,"is_corresponding":false},{"id":618865,"name":"Qiang Feng","orcid":"0000-0002-3665-3914","position":3,"is_corresponding":false},{"id":285060,"name":"Jonathan Wilhelm","orcid":"0000-0003-4055-123X","position":4,"is_corresponding":false},{"id":285059,"name":"Xu Wang","orcid":"0000-0002-8925-5645","position":5,"is_corresponding":false},{"id":618866,"name":"Wei Li","orcid":"0000-0002-4264-1864","position":6,"is_corresponding":false},{"id":252142,"name":"Jian Wang","orcid":"0000-0002-9482-5227","position":7,"is_corresponding":false},{"id":600108,"name":"Agnieszka Cholka","orcid":null,"position":8,"is_corresponding":false},{"id":288259,"name":"Yang-Xin Fu","orcid":"0000-0003-0956-3654","position":9,"is_corresponding":false},{"id":618867,"name":"Baran D. Sumer","orcid":"0000-0002-8371-4388","position":10,"is_corresponding":false},{"id":461262,"name":"Hongtao Yu","orcid":"0000-0002-8861-049X","position":11,"is_corresponding":false},{"id":285069,"name":"Jinming Gao","orcid":"0000-0003-0726-5098","position":12,"is_corresponding":false},{"id":285062,"name":"Suxin Li","orcid":"0000-0001-6466-6854","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:42:12.871665Z","pmid":"33558734","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}