Normalization of Tumor Vessels by Lenvatinib‐Based Metallo‐Nanodrugs Alleviates Hypoxia and Enhances Calreticulin‐Mediated Immune Responses in Orthotopic HCC and Organoids

Abstract Immunocheckpoint inhibitors combined with Lenvatinib is the first line treatment for hepatocellular carcinoma (HCC), but their potency is hampered by the low response rate and adverse events. Herein, a targeted therapeutic strategy through the coassembly of Lenvatinib, Adriamycin, Fe3+ ion, and a natural polyphenol (metallo‐nanodrugs) is presented by coordination effect for potentiating tumor vascular normalization and systematic chemo‐immunotherapy to effectively inhibit the progression of HCC in both orthotopic model and patients‐derived organoids. In mice with orthotopic HCC, the obtained metallo‐nanodrugs efficiently increase the drug accumulation in orthotopic tumors and can respond to acidic tumor environment. The promotion of tumor vascular normalization by metallo‐nanodrugs is observed, which enhances the infiltrating T lymphocytes in tumor, and reinforces the calreticulin‐mediated antitumor immunity through alleviating hypoxia, reducing regulatory T cells, and down‐regulating PDL1 expression of tumors. The excellent therapeutic efficiency with complete remission of orthotopic tumors (3/6) and long‐term survival of mice (4/6, 42 days) are also achieved. Furthermore, the excellent therapeutic effect of metallo‐nanodrugs is also validated in 5 patient‐derived organoids, and hence can provide a marvelous systemic chemo‐immunotherapy strategy for enhancing HCC treatment.