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In this study, several cationic amphiphilic polypeptides were obtained to investigate their architecture\u2010dependent cytotoxicity and ICD\u2010inducing properties. Among these candidates, the random copolymer PRP was identified as the most effective lead polymer, exhibiting superior tumor cell\u2010killing activity and selectivity compared with the corresponding block copolymer and homopolymer analogues. Mechanistic investigations showed that PRP disrupted tumor cell membranes and induced necrotic cell death. In addition, PRP triggered a pronounced ICD response by impairing mitochondrial function and increasing intracellular reactive oxygen species levels. In multiple murine models, PRP effectively suppressed tumor progression, metastasis, and recurrence through direct oncolysis and activation of antitumor immune responses, while markedly reducing tumor\u2010associated bone damage. These findings demonstrate that PRP functions as a potent ICD\u2010inducing polypeptide with considerable potential for the immunotherapy of metastatic bone tumors.<\/jats:p>","DOI":"10.1002\/adhm.71767","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:38:11Z","timestamp":1790325491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cationic Amphiphilic Polypeptides With Immunogenic Cell Death Inducing Activity for Inhibition of Metastatic Bone Cancer"],"prefix":"10.1002","author":[{"given":"Yao","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Bone and Joint Surgery The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Polymer Science and Technology Changchun Institute of Applied Chemistry 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