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Herein, we introduce a dual\u2010locked Pt(IV) prodrug designed for tumor\u2010specific activation, combining platinum\u2010based chemotherapy with TLR7\/8\u2010mediated immunotherapy. The prodrug features a \u03b3\u2010glutamyl\u2010caged TLR7\/8 agonist as an axial ligand, enabling sequential activation by elevated glutathione (GSH) and \u03b3\u2010glutamyltranspeptidase (GGT) in the tumor microenvironment. Reduction of the Pt(IV) core releases cisplatin and depletes intracellular reductants, amplifying reactive oxygen species to trigger synergistic ferroptosis and apoptosis. Concurrently, GGT\u2010cleaved axial ligand activates tumor\u2010associated macrophages and dendritic cells, repolarizing immunosuppressive M2\u2010like macrophages to pro\u2010inflammatory M1\u2010like phenotypes while recruiting effector and memory T cells. In murine models, the Pt(IV) prodrug demonstrated potent antitumor efficacy by confining immune activation to malignant tissues, eradicating primary tumors, and establishing durable protective immunity against recurrence. This spatiotemporally controlled dual\u2010release strategy minimizes systemic toxicity while synergizing chemotherapy and immunotherapy, offering a transformative approach for targeted cancer therapy.<\/jats:p>","DOI":"10.1002\/anie.202505930","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T02:55:12Z","timestamp":1746500112000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Evoking Simultaneous Ferroptosis and Apoptosis by a Dual\u2010Locked Platinum (IV) Prodrug for Synergistic Chemo\u2010immunotherapy"],"prefix":"10.1002","volume":"64","author":[{"given":"He","family":"Meng","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Wen","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Xu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuruiqi","family":"Luo","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenkai","family":"Lin","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Lu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Lu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Xiong","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiao","family":"Xu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong\u2010Wan","family":"Mao","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xia","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME School of Chemistry Sun Yat\u2010Sen University  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc749"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr400460s"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr020010d"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00757F"},{"key":"e_1_2_7_5_1","first-page":"148","volume":"375","author":"Deo K. 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