Ferroptosis‐Enhanced Immunotherapy with an Injectable Dextran‐Chitosan Hydrogel for the Treatment of Malignant Ascites in Hepatocellular Carcinoma

Abstract Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. 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‐OD) is designed to load sulfasalazine (SSZ), an FDA‐approved drug with ferroptosis‐inducing ability, for effective tumor‐killing and activation of anti‐tumor immunity. Compared to free SSZ, SSZ‐loaded CH‐OD (CH‐OD‐SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH‐OD‐SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH‐OD‐SSZ hydrogel induces the repolarization of macrophages to an M1‐like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH‐OD‐SSZ hydrogel and anti‐programmed cell death protein 1 (PD‐1) immunotherapy achieves more than 50% ascites regression and generates long‐term immune memory. Collectively, CH‐OD‐SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti‐PD‐1 immunotherapy.