Multi-faceted nanodrug reinforcing metalloimmunotherapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) poses a major therapeutic challenge due to its immunosuppressive microenvironment and limited efficacy of current immunotherapies. While immune checkpoint inhibitors (ICIs) improve survival in some patients, their effectiveness is hindered by poor T-cell infiltration and tumor vascular abnormalities. To address this, we investigated the therapeutic potential of combining Lenvatinib with Co, a strategy aimed at simultaneously targeting PD-L1 expression and activating antitumor immunity. Mechanistic studies revealed that Lenvatinib inhibits MNK1/eIF4E-mediated PD-L1 translation, while Co induce ROS-dependent DNA damage and activate the cGAS-STING pathway, triggering immunogenic cell death (ICD) in HCC cells. Building on these findings, we developed pH-modulated self-assembled nanoclusters (Co + Len@OVA) by co-assembling ovalbumin, Lenvatinib, and Co. These nanoclusters exhibited tumor-selective accumulation and enhanced vascular normalization, which promoted anti-PD1 antibody penetration into tumors. In mouse HCC models, Co + Len@OVA combined with anti-PD1 therapy achieved a significant reduction in tumor volume, significantly outperforming monotherapies. This combination also reshaped the immunosuppressive microenvironment by enhancing DCs' maturation, increasing cytotoxic CD8 T cells, and suppressing Tregs infiltration. Our study establishes a combinatorial approach that integrates metalloimmunotherapy with vascular modulation, offering a clinically translatable strategy for unresectable HCC.