{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:02:07Z","timestamp":1785160927030,"version":"3.55.0"},"reference-count":51,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22177068"],"award-info":[{"award-number":["22177068"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["24ZR1491100"],"award-info":[{"award-number":["24ZR1491100"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFF1203005"],"award-info":[{"award-number":["2022YFF1203005"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tumor-specific activation of the stimulator of the interferon genes (STING) pathway is essential for maximizing antitumor efficacy while minimizing systemic toxicity of STING agonists. Conjugating STING agonists with tumor-targeting warheads has emerged as a promising strategy in cancer immunotherapy. In this study, we designed and synthesized a series of fibroblast activation protein (FAP)-targeting platinum (Pt)(IV)-centered STING agonist conjugates by esterifying the two axial hydroxyls of Pt(IV) species with STING agonist MSA-2 and the FAP warhead, respectively. Among the synthesized conjugates, 21b exhibited picomolar binding affinity to FAP and preferentially accumulated in 3T3-hFAP cells. Under hypoxic tumor conditions, these conjugates release the active Pt(II) species to induce tumor cell death and simultaneously liberate MSA-2 to activate the STING\/IFN-mediated antitumor immune response. In colon tumor-bearing mice, 21b mainly distributed in tumor tissue and showed significantly enhanced antitumor activity and reduced toxicity. Compared to MSA-2 alone, it promoted more CD8+ T-cell infiltration and reduced FAP+ cell populations in tumors. Importantly, it selectively elevated TNF-\u03b1 and IP-10 levels in tumor tissue without increasing serum cytokine levels, indicating tumor-specific STING pathway activation. These findings provide strong proof of concept for FAP-targeted Pt(IV)\u2013STING agonist conjugates as a novel tumor-specific metalloimmunotherapy.<\/jats:p>","DOI":"10.1021\/jacsau.6c00442","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:17:13Z","timestamp":1781810233000},"page":"3877-3888","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of FAP-Targeted\nPlatinum(IV)-Esterified\nSTING Agonist as Small-Molecule Dual Prodrug Conjugates for Tumor-Specific\nMetalloimmunotherapy"],"prefix":"10.1021","volume":"6","author":[{"given":"Ende","family":"He","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Fan","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilan","family":"Song","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7205-9202","authenticated-orcid":true,"given":"Ao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]},{"name":"Shanghai Pharmaceuticals Holding Co., Ltd. , , ,","place":["Shanghai, P. R. China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-8740","authenticated-orcid":true,"given":"Chunyong","family":"Ding","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]},{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]},{"name":"Shanghai Pharmaceuticals Holding Co., Ltd. , , ,","place":["Shanghai, P. R. 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Med."},{"issue":"10","key":"2026072709071073500_cit4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110150","article-title":"Cyclic GMP-AMP Displays Mucosal Adjuvant\nActivity in Mice","volume":"9","author":"S\u030ckrnjug","year":"2014","journal-title":"PLoS One"},{"issue":"7","key":"2026072709071073500_cit5","doi-asserted-by":"publisher","first-page":"3077","DOI":"10.1158\/0008-5472.CAN-08-2281","article-title":"Chemokine\nExpression\nin Melanoma Metastases Associated with CD8+ T-Cell Recruitment","volume":"69","author":"Harlin","year":"2009","journal-title":"Cancer Res."},{"key":"2026072709071073500_cit6","doi-asserted-by":"publisher","first-page":"795401","DOI":"10.3389\/fimmu.2021.795401","article-title":"The cGAS\/STING Pathway:\nA Novel Target\nfor Cancer Therapy","volume":"12","author":"Gan","year":"2022","journal-title":"Front. 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Ed."},{"issue":"3","key":"2026072709071073500_cit26","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1007\/s10555-020-09909-3","article-title":"The Role of Fibroblast\nActivation Protein in Health\nand Malignancy","volume":"39","author":"Fitzgerald","year":"2020","journal-title":"Cancer Metastasis Rev."},{"issue":"7","key":"2026072709071073500_cit27","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1007\/s13346-023-01308-9","article-title":"Targeting Fibroblast\nActivation Protein (FAP): Advances in CAR-T Cell, Antibody, and Vaccine\nin Cancer Immunotherapy","volume":"13","author":"Shahvali","year":"2023","journal-title":"Drug Delivery Transl.\nRes."},{"issue":"3","key":"2026072709071073500_cit28","doi-asserted-by":"publisher","first-page":"2476","DOI":"10.3892\/mmr.2016.4868","article-title":"Targeting\nof Cancer-Associated Fibroblasts Enhances the Efficacy of Cancer Chemotherapy\nby Regulating the Tumor Microenvironment","volume":"13","author":"Li","year":"2016","journal-title":"Mol.\nMed. Rep."},{"issue":"32","key":"2026072709071073500_cit29","doi-asserted-by":"publisher","first-page":"4343","DOI":"10.1038\/s41388-018-0275-3","article-title":"Pro-Tumorigenic Roles of Fibroblast Activation Protein\nin Cancer: Back to the Basics","volume":"37","author":"Pure\u0301","year":"2018","journal-title":"Oncogene"},{"issue":"6","key":"2026072709071073500_cit30","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.3390\/cancers15061889","article-title":"Novel Generation of FAP Inhibitor-Based\nHomodimers for Improved Application in Radiotheranostics","volume":"15","author":"Martin","year":"2023","journal-title":"Cancers"},{"issue":"16","key":"2026072709071073500_cit31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2101852118","article-title":"An Ultra-High-Affinity\nSmall Organic\nLigand of Fibroblast Activation Protein for Tumor-Targeting Applications","volume":"118","author":"Millul","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"7","key":"2026072709071073500_cit32","doi-asserted-by":"publisher","first-page":"3053","DOI":"10.1021\/jm500031w","article-title":"Extended Structure\u2013Activity\nRelationship and Pharmacokinetic Investigation of (4-Quinolinoyl)Glycyl-2-Cyanopyrrolidine\nInhibitors of Fibroblast Activation Protein (FAP)","volume":"57","author":"Jansen","year":"2014","journal-title":"J. Med. Chem."},{"issue":"9","key":"2026072709071073500_cit33","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1038\/s41551-021-00728-7","article-title":"Nanoparticle-Mediated Convection-Enhanced Delivery\nof a DNA Intercalator to Gliomas Circumvents Temozolomide Resistance","volume":"5","author":"Wang","year":"2021","journal-title":"Nat. Biomed. 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