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

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. Conclusions: SA represents a novel intracellular PD-L1-targeted nanoplatform that promotes lysosome-mediated PD-L1 clearance, remodels the tumor immune milieu, and demonstrates superior antitumor performance compared to PD-L1 antibodies. This dual mechanism addresses key limitations of current ICB therapies and supports further clinical translation.