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Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half\u2010life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)\u2010responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES\u2010Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high\u2010level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010stimulated Fenton\u2010like reaction together with CA\u2010stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli\u2010dissociation of ECPCP, forming a positive feedback therapy loop against tumor self\u2010alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application.\n                  <\/jats:p>","DOI":"10.1002\/advs.202401047","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T17:54:01Z","timestamp":1712166841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["A Self\u2010Amplifying ROS\u2010Responsive Nanoplatform for Simultaneous Cuproptosis and Cancer Immunotherapy"],"prefix":"10.1002","volume":"11","author":[{"given":"Hangyi","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics China Pharmaceutical University  Nanjing 211198 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine  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