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Platinum\u2010based metallodrugs, especially oxaliplatin (Oxa), serve as first\u2010line chemotherapeutics in clinical practice. However, their clinical utility is greatly restricted by acquired drug resistance, insufficient tumor accumulation, and weak immunostimulatory capacity. Herein, we synthesize a platinum\u2013ruthenium nanohybrid prodrug (denoted as PR) via self\u2010assembly, which integrates Oxa PR and ruthenium ions for synergistic chemo\u2010\/chemodynamic\u2010\/immunotherapy of hypoxic tumors. The PR nanohybrid possesses intrinsic multi\u2010enzyme activities (catalase, peroxidase, and glutathione peroxidase), enabling efficient oxygen generation, hydroxyl radical production, and glutathione depletion. These cascading events enhance chemosensitivity, trigger robust immunogenic cell death, and activate the cGAS\u2010STING signaling pathway. Furthermore, nanocatalytic modulation of the hypoxic TME alleviates hypoxia\u2010driven immunosuppression, downregulates PD\u2010L1 expression on cancer cells, and reinforces antitumor immune responses. In vitro and in vivo investigations demonstrate that PR nanohybrid exhibits superior anticancer efficacy over free Oxa and displays promising potential in combination with PD\u20101 blockade therapy. These findings highlight the PR nanohybrid as a versatile TME\u2010modulating platform for hypoxic tumor treatment, offering a novel strategy to advance platinum\u2010based combination cancer therapy.<\/jats:p>","DOI":"10.1002\/adhm.71484","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T10:52:35Z","timestamp":1784976755000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Multiple Enzyme\u2010Mimetic Platinum\u2013Ruthenium Nanohybrid Prodrug Potentiates Chemo\u2010\/Chemodynamic\u2010\/Immuno\u2010Therapy of Hypoxic Tumors"],"prefix":"10.1002","volume":"15","author":[{"given":"Huixi","family":"Yi","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Bioscience and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhua","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Xue","sequence":"additional","affiliation":[{"name":"College of Chemistry Shandong Normal University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixiong","family":"Zhan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyou","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyong","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-4872","authenticated-orcid":false,"given":"Jianliang","family":"Shen","sequence":"additional","affiliation":[{"name":"National Engineering Research Center of Ophthalmology and Optometry Eye Hospital Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3940-8911","authenticated-orcid":false,"given":"Dong\u2010Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2023.215439"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00366"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1287"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds074"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42004\u2010022\u201000661\u2010z"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756\u20109966\u201028\u2010144"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.220"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1590"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2010.07.001"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.1c00635"},{"issue":"4","key":"e_1_2_10_12_1","first-page":"1205","article-title":"Clinical Pharmacokinetics of Oxaliplatin: A Critical Review","volume":"6","author":"Graham M. 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