{"doi":"10.1021/jacs.5c03455","title":"Long-Lived Immunogenic Cell Death Induced by a Water-Soluble Redox Active Au(I) Bis-N-Heterocyclic Carbene","abstract":"Immunogenic cell death (ICD) is a form of regulated cell death that engages the immune system by releasing damage-associated molecular patterns, making it a promising target for cancer immunotherapy. Presented here is the synthesis and evaluation of a series of asymmetric redox-active water-soluble Au(I) bis-N-heterocyclic carbenes (Au(I) bis-NHCs). We explore the structure–activity relationships between redox activity, water solubility and ICD induction, building on our previous work with a redox-active Au(I) bis-NHC ( 1 ) that effectively induced ICD but suffered from poor water solubility. To overcome this limitation, we synthesized several water-soluble redox-active Au(I) bis-NHCs, derivatives 2–4, by modifying the imidazole moiety. Compound 2 was identified as the lead, balancing water solubility and ICD induction efficacy. This compound, featuring a naphthoquinone moiety, and was found to generate reactive oxygen species (ROS) and trigger key ICD biomarkers, including calreticulin (CRT) translocation, ATP release, and high mobility group box 1 (HMGB1) secretion. A control compound lacking the redox active naphthoquinone failed to elicit these ICD markers or promote ROS production. Across the series 1–4 a correlation was observed between ROS generation and ICD biomarker expression. In vivo studies in syngeneic immunocompetent mice demonstrated that compound 2 not only prevents CT26 colorectal cancer tumor growth upon challenge with live cancer cells but also elicits a long-lived immune response upon rechallenge 12 months later.","journal":"Journal of the American Chemical Society","year":2025,"id":510842,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9702,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392369,"name":"Sajal Sen","orcid":"0000-0002-1189-4156","position":1,"is_corresponding":false},{"id":1091458,"name":"Esther Y. Maier","orcid":"0000-0002-6242-3389","position":2,"is_corresponding":false},{"id":1368575,"name":"M. Manuela M. da Mota","orcid":null,"position":3,"is_corresponding":false},{"id":640034,"name":"Miae Won","orcid":"0000-0002-1656-6362","position":4,"is_corresponding":false},{"id":257598,"name":"Jiexi Li","orcid":"0000-0003-1508-5732","position":5,"is_corresponding":false},{"id":438420,"name":"Jonathan F. Arambula","orcid":"0000-0003-2342-8440","position":6,"is_corresponding":false},{"id":1368576,"name":"V.M. Lynch","orcid":null,"position":7,"is_corresponding":false},{"id":638388,"name":"Jong Seung Kim","orcid":"0000-0003-3477-1172","position":8,"is_corresponding":false},{"id":7904,"name":"Ronald A. DePinho","orcid":"0000-0002-5625-577X","position":9,"is_corresponding":false},{"id":547157,"name":"Brent L. Iverson","orcid":"0000-0001-7974-3605","position":10,"is_corresponding":false},{"id":107373,"name":"Jonathan L. Sessler","orcid":"0000-0002-9576-1325","position":11,"is_corresponding":false},{"id":1016385,"name":"Matthew S. Levine","orcid":"0000-0002-2622-2678","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T02:47:50.575618Z","pmid":"40570165","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":[]}