Paving the way for immunotherapy: Simvastatin-primed dual-targeting NPTAC overcomes immune resistance in hepatocellular carcinoma.

Immune checkpoint blockade (ICB)-based regimens, tyrosine kinase inhibitors, and transcatheter arterial chemoembolization (TACE) are major clinical options for unresectable hepatocellular carcinoma (HCC), yet their efficacy remains limited by poor tumor targeting, low response rates, insufficient immune activation, and systemic toxicity. To address these challenges, we establish a "Pave the Way Strategy" combining simvastatin (SIM) with a dual-targeted nanoparticle-mediated targeting chimera (Hs/αPD-L1-NPTAC). Oral SIM acts as a dual-function paving agent, it upregulates hepatic low-density lipoprotein receptor (LDLR) expression to enhance nanoparticle delivery, and depletes tumor cell membrane cholesterol to increase rigidity, boosting dendritic cell phagocytosis and antigen presentation. The LDLR/PD-L1 dual-targeted Hs/αPD-L1-NPTAC enables precise HCC targeting and synchronous intracellular functions. It releases paclitaxel (PTX), promotes intracellular downregulation of PD-L1 and LDLR through endolysosomal trafficking, and cooperates with SIM to establish dual metabolic intervention by simultaneously suppressing cholesterol synthesis and limiting exogenous cholesterol uptake. In immunocompetent orthotopic HCC models, this strategy potently inhibits tumor growth and lung metastasis, prolongs survival, enhances CD8+ cytotoxicity T cell, and remodels the immunosuppressive tumor microenvironment. This paradigm provides a promising approach to overcome ICB resistance and enable precision immunotherapy for HCC.