LAUSR

Although immunotherapy of hepatocellular carcinoma using immune checkpoint inhibitors has achieved certain success, only a subset of patients benefits from this therapeutic strategy. The combination of immunostimulatory chemotherapeutics represents a promising strategy to enhance the effectiveness of immunotherapy. However, it is hampered by the poor delivery of conventional chemotherapeutics. Here, it is shown that H‐ferritin nanocages loaded with doxorubicin (DOX@HFn) show potent chemo‐immunotherapy in hepatocellular carcinoma tumor models. DOX@HFn is constructed with uniform size, high stability, favorable drug loading, and intracellular acidity‐driven drug release. The receptor‐mediated targeting of DOX@HFn to liver cancer cells promote cellular uptake and tumor penetration in vitro and in vivo. DOX@HFn triggers immunogenic cell death to tumor cells and promotes the subsequent activation and maturation of dendritic cells. In vivo studies in H22 subcutaneous hepatoma demonstrate that DOX@HFn significantly inhibits the tumor growth with >30% tumors completely eliminated, while alleviating the systemic toxicity of free DOX. DOX@HFn also exhibits robust antitumor immune response and tumoricidal effect in a more aggressive Hepa1‐6 orthotopic liver tumor model, which is confirmed by the in situ magnetic resonance imaging and transcriptome sequencing. This study provides a facile and robust strategy to improve therapeutic efficacy of liver cancer.