Multi-faceted nanodrug reinforcing metalloimmunotherapy for hepatocellular carcinoma

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.