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This nanosystem uses Mannose-PEG-s-s-PCL\/CDM-PEG-PCL as carriers to co-load the ferroptosis inducer IKE, STING agonist diABZI, and anti-PD-1 antibody (aPD-1), enabling tumor microenvironment-specific drug release and lymph node-targeted delivery.\n                    <jats:bold>Results:<\/jats:bold>\n                    In\u00a0vitro experiments demonstrated rapid drug release under acidic\/high GSH conditions, inducing ferroptosis in bladder cancer cells and activating dendritic cells through the release of danger signals such as HMGB1. It showed marked enrichment of the nanosystem in tumors and draining lymph nodes, suppressing orthotopic bladder tumor growth (94.5% inhibition rate) and lung metastasis (92% reduction in metastatic foci) while extending median survival in mice to 35 d. Mechanistic studies revealed that ferroptosis-induced immunogenic cell death synergized with STING pathway activation to enhance CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and granzyme B expression, while blocking the PD-1\/PD-L1 axis alleviated immunosuppression. Furthermore, the treatment group exhibited long-term immune memory, effectively preventing tumor recurrence.\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    This study provides an innovative multi-mechanism synergistic strategy to overcome immunotherapy resistance in bladder cancer, demonstrating significant clinical translation potential.\n                  <\/jats:p>","DOI":"10.34133\/cbsystems.0458","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T10:24:32Z","timestamp":1761733472000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":4,"title":["Nano-Immunotherapy Synergizing Ferroptosis and STING Activation in Metastatic Bladder Cancer"],"prefix":"10.34133","volume":"7","author":[{"given":"Hang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."},{"name":"Translational Medicine Laboratory, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."},{"name":"Institute of Urology, Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangdie","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Urology, Huashan Hospital, \rFudan University, Shanghai 200040, China."},{"name":"Fudan Institute of Urology, Huashan Hospital, \rFudan University, Shanghai 200040, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkai","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qimeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2023-076743","article-title":"Advances in diagnosis and treatment of bladder cancer","volume":"384","author":"Lopez-Beltran A","year":"2024","unstructured":"Lopez-Beltran A, Cookson MS, Guercio BJ, Cheng L. 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