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.　©　2023　Wiley-VCH　GmbH.