Injectable Thermosensitive Hydrogel Targeting STAT3 Reprograms Neutrophils to Amplify Anti‐Tumor Immunity Post‐Radiofrequency Ablation in HCC

ABSTRACT Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) carries a high risk of recurrence due to residual tumors and the immunosuppressive tumor microenvironment. This study identifies that incomplete RFA activates the JAK2/STAT3 pathway in tumor‐associated neutrophils (TANs), polarizing them toward immunosuppressive phenotypes. In vitro, icaritin (ICT) inhibits TAN survival and migration, and reverses the immunosuppressive phenotype by suppressing STAT3 phosphorylation. To enable localized delivery, we developed an injectable hydrogel (HP@ICT) by leveraging the interfacial complexation of hydroxypropyl‐β‐cyclodextrin and the thermosensitive gelation of poloxamer 407. It is injected via the ablation needle into the residual cavity and undergoes in situ gelation, overcoming post‐ablation drug delivery barriers to enable sustained release of ICT. In vivo, HP@ICT effectively suppresses immunosuppressive TANs, reduces the proportion of PMN‐MDSCs, and promotes the infiltration and activation of CD8 + T cells without systemic toxicity. The hydrogel co‐delivering ICT and PD‐L1 inhibitor synergistically eliminates residual tumors and liver metastases post‐RFA by inducing systemic anti‐tumor immunity. Multi‐omics analyses reveal complementary mechanisms of ICT, which inhibits PD‐L1 expression in TANs, disrupts TAN‐tumor adhesion, and suppresses unsaturated fatty acid metabolism. Overall, with accessible materials and seamless integration with RFA, this strategy optimizes RFA efficacy, providing a safe and translational solution for HCC recurrence.