Dual-action PD-L1 depletion in tumor cells and macrophages revitalizes immune attack in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) responds poorly to immune checkpoint blockade and readily develops immune resistance. Here, we engineered a PD-L1-targeted supramolecular peptide (PBP-SH) to improve immunotherapy efficacy in HCC. PBP-SH, which incorporated both HSC70-binding and PD-L1-binding motifs, was synthesized using solid-phase peptide synthesis. Subsequently, it was assembled into nanoparticles via gold-mediated self-assembly and further cloaked with PD-1-overexpressing T cell membranes to generate SupraPD1. SupraPD1 specifically recognized PD-L1, enabling targeted delivery in PD-L1-enriched microenvironments. Under GSH-responsive conditions, SupraPD1 released PBP-SH, which bound to intracellular PD-L1 through the HSC70-mediated lysosomal pathway, thereby effectively reducing PD-L1 expression in both tumor cells and macrophages. In anti-tumor efficacy studies, SupraPD1 demonstrated significantly higher tumor inhibition rates than anti-PD-L1 antibodies in both orthotopic HCC mouse models and ICIs-resistant HCC models. Moreover, SupraPD1 enhanced the infiltration of anti-tumor immune cells, including dendritic cells, natural killer cells, granzyme B⁺ cytotoxic T lymphocytes (CTLs), and IFN-γ⁺ CTLs, while simultaneously reducing the proportion of regulatory T cells (Tregs). This immune modulation led to prolonged survival in tumor-bearing mice. Additionally, SupraPD1 exhibited favorable biosafety profiles. We propose a PD-L1-targeting platform that suppresses HCC progression by depleting PD-L1 in tumor cells and macrophages, demonstrating potential for further clinical translation.