Cholesterol Targeted Catalytic Hydrogel Fueled by Tumor Debris can Enhance Microwave Ablation Therapy and Anti‐Tumor Immune Response

Abstract The immunosuppressive residual tumor microenvironment (IRTM) is a key factor in the high recurrence and metastasis rates of hepatocellular carcinoma (HCC) after microwave ablation (MWA). Cholesterol‐rich tumor fragments significantly contribute to IRTM deterioration. This study developed a cholesterol‐targeted catalytic hydrogel, DA‐COD‐OD‐HCS, to enhance the synergy between MWA and immune checkpoint inhibitors (ICIs) for HCC treatment. Cholesterol oxidase (COD), modified with dimethyl maleic anhydride (DA) for release in acidic IRTM, is used to degrade cholesterol. Oxydextran (OD) and hemin‐chitosan (HCS) formed a dual network gel, ensuring long‐term fixation of COD and hemin in the IRTM post‐MWA. In both in vitro and in vivo HCC models, DA‐COD‐OD‐HCS effectively released COD, degraded cholesterol, and induced tumor cell ferroptosis, enhancing the antitumor immune response. Combined with anti‐PD‐L1 immunotherapy, this strategy inhibited primary tumor growth and distant metastases, without side effects on adjacent tissues. This work highlights that cholesterol‐targeting catalytic hydrogels fueled by tumor debris can significantly improve the efficacy of MWA and ICIs, offering a novel therapeutic approach for HCC.