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Platinum\u2010based chemotherapeutics, while foundational in oncology, exemplify this challenge because of their indiscriminate action on both cancerous and healthy cells, leading to detrimental side effects. Inspired by the versatile coordination chemistry in metalloproteins, we developed a platinum(IV)\u2010based metallo\u2010stapling strategy to construct tumor\u2010specific metalloprodrugs. This approach leverages the Pt(IV) complex dually as a chemotherapeutic agent and a structural staple that conformationally rigidifies an epidermal growth factor receptor (EGFR)\u2010targeting ligand. The resultant macrocyclic metalloprodrug exhibits precise targeting of EGFR\u2010overexpressing malignancies, achieving in vivo tumor platinum accumulation 7\u2010fold higher than the parent Pt(II) complex and 5\u2010fold greater than its linear counterpart due to superior metabolic stability and efficient receptor\u2010mediated uptake conferred by the macrocyclic architecture. Upon reaching the tumor microenvironment, the construct undergoes dual\u2010payload release to liberate platinum drug and the IDO\u20101 inhibitor NLG919 analogue (NLG), eliciting a robust immunogenic cell death cascade while simultaneously reversing immunosuppression. Furthermore, a combination with an aPD\u2010L1 immune checkpoint blockade produces a marked synergistic antitumor response. This work establishes Pt(IV)\u2010directed metallo\u2010stapling as a versatile platform for precision cancer therapy, offering a generalizable strategy to chemically engineer a broad range of metalloprodrugs with enhanced tumor selectivity and biosafety.<\/jats:p>","DOI":"10.1002\/anie.8875420","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:46:41Z","timestamp":1782200801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Platinum(IV) Metallo\u2010Stapling Approach to Tumor\u2010Specific Prodrugs for Targeted Chemo\u2010Immunometabolic Cancer Therapy"],"prefix":"10.1002","volume":"65","author":[{"given":"Li","family":"Jiang","sequence":"first","affiliation":[{"name":"Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs School of Life Science and Engineering Southwest Jiaotong University  Chengdu Sichuan People's Republic of 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