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Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH\u2010OD) is designed to load sulfasalazine (SSZ), an FDA\u2010approved drug with ferroptosis\u2010inducing ability, for effective tumor\u2010killing and activation of anti\u2010tumor immunity. Compared to free SSZ, SSZ\u2010loaded CH\u2010OD (CH\u2010OD\u2010SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH\u2010OD\u2010SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH\u2010OD\u2010SSZ hydrogel induces the repolarization of macrophages to an M1\u2010like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH\u2010OD\u2010SSZ hydrogel and anti\u2010programmed cell death protein 1 (PD\u20101) immunotherapy achieves more than 50% ascites regression and generates long\u2010term immune memory. Collectively, CH\u2010OD\u2010SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti\u2010PD\u20101 immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.202300517","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T07:22:09Z","timestamp":1683098529000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Ferroptosis\u2010Enhanced Immunotherapy with an Injectable Dextran\u2010Chitosan Hydrogel for the Treatment of Malignant Ascites in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"10","author":[{"given":"Jingshu","family":"Meng","sequence":"first","affiliation":[{"name":"Cancer Center Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 P. R. 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