Icaritin Exacerbates Mitophagy and Synergizes with Doxorubicin to Induce Immunogenic Cell Death in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) resistant to both chemotherapy and immunotherapy is among the deadliest malignancies. Doxorubicin widely used in transarterial chemotherapy in HCC can induce immunogenic cell death (ICD), but the resulting immunogenicity is still weak. We aim to seek a strategy for improving the efficacy of ICD in HCC based on an immunoregulatory drug called icaritin. Icaritin induced mitophagy and apoptosis to provoke ICD both in mouse Hepa1-6 and human Huh7 HCC cells. A combination of icaritin and doxorubicin with a molar ratio of 1:2 played a synergistic role in ICD induction. The poly lactic-<i>co</i>-glycolic acid (PLGA)-polyethylene glycol (PEG)-aminoethyl anisamide (AEAA) nanoparticle (NP) targeted codelivery of icaritin and doxorubicin remodeled the immunosuppressive tumor microenvironment and triggered a robust immune memory response, which efficiently improved anti-HCC effect at an early stage in mouse HCC model. In addition, the combo PLGA-PEG-AEAA NP together with lenvatinib significantly prolonged survival time of mice at the advanced stage of HCC. Collectively, our findings reveal an anti-HCC mechanism of icaritin on mitophagy and provide an effective immune-based therapeutic strategy for HCC.