A bifunctional peptide–selenium nanocomposite for lysosomal degradation of PD-L1 and enhanced cancer immunotherapy

作者：Yang Wang, Jun Feng, Jin Yan, Weiming You, Siqi Yan · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1678911 · 被引用次数：2 · 研究领域：Selenium in Biological Systems、Cancer Immunotherapy and Biomarkers、Nanoplatforms for cancer theranostics

Background Immune checkpoint blockade (ICB) therapies that inhibit PD-1/PD-L1 signaling have revolutionized oncology, yet their benefits are constrained by limited penetration into tumor tissues, inability to eliminate intracellular PD-L1, and the emergence of resistance pathways. Approaches aimed at promoting intracellular PD-L1 degradation and reshaping the tumor immune microenvironment hold promise for overcoming these therapeutic barriers. Methods A bifunctional therapeutic peptide a capable of binding cytosolic PD-L1 and the molecular chaperone HSC70 was synthesized to facilitate chaperone-mediated autophagy–dependent lysosomal degradation of PD-L1. To improve stability and tumor delivery, peptide a was self-assembled with nano-selenium to form SA. SA was characterized by TEM, DLS, and UV–vis spectroscopy. Binding affinity was validated by ITC. Cellular uptake, PD-L1 degradation, and lysosomal trafficking were assessed via flow cytometry, western blotting, and immunofluorescence. Antitumor efficacy was evaluated in CT26 models and MC38 spheroid assays, with mechanistic analysis performed using immunohistochemistry and flow cytometry. Safety was comprehensively assessed. Results SA exhibited uniform spherical morphology (~35 nm) and excellent stability. In vitro studies demonstrated enhanced cellular uptake compared to free peptide and dose-dependent PD-L1 degradation (31.1% reduction at 0.6 μg/mL), which was significantly attenuated by lysosomal inhibition, confirming th...