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However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti\u2010tumor immune responses. Herein, we present the first iridium(III)\u2010based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS\u2013STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)\u2010based oncosis\u2010inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug\u2010resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis\/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt\u2010DNA damage, leading to robust activation of the cGAS\u2013STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)\u2010based immunogenic oncosis inducers were able to effectively kill drug\u2010resistant cancer cells and enhance the anticancer immune response in tumor mouse models.<\/jats:p>","DOI":"10.1002\/anie.202521242","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:29:51Z","timestamp":1765204191000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Boosting Cancer Chemoimmunotherapy with Mitochondria\u2010Targeting Iridium(III)\u2010Based Immunogenic Oncosis Inducers"],"prefix":"10.1002","volume":"65","author":[{"given":"Jun","family":"Shu","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Bioinorganic and Synthetic Chemistry State Key Laboratory of Anti\u2010Infective Drug Discovery and Development Guangdong Basic Research Center of Excellence for Functional Molecular Engineering School of Chemistry Guangdong Provincial Key Laboratory of Digestive Cancer Research The Seventh Affiliated Hospital Sun Yat\u2010Sen University  Guangzhou 510006 P.R. 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