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Multi-faceted nanodrug reinforcing metalloimmunotherapy for hepatocellular carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths, with limited options for unresectable cases. Immunotherapies show promise but are hindered by the immunosuppressive tumor microenvironment (TME). This study developed cobalt-Lenvatinib combination nanoclusters (Co+Len@OVA) to enhance HCC immunotherapy. These nanoclusters, formed by self-assembling ovalbumin, Lenvatinib, and cobalt ions, effectively inhibited HCC progression and reduced immunosuppression. They accumulated at tumor sites, inducing immunogenic cell death and activating the STING-IFNβ pathway, leading to a potent antitumor immune response. Additionally, they normalized tumor vasculature, improving anti-PD1 antibody retention and penetration. Combining Co+Len@OVA with anti-PD1 therapy significantly reduced HCC tumor volume more effectively than conventional treatments. Our study shows that Co+Len@OVA nanoclusters offer a promising treatment for HCC, particularly when surgery is not an option. They combine cobalt-mediated metalloimmunotherapy with Lenvatinib and boost the effectiveness of anti-PD1 therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE286376 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background and purpose: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. Basic procedures: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Main findings: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Principal conclusions: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

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Multi-faceted nanodrug reinforcing metalloimmunotherapy for hepatocellular carcinoma

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