Reprogramming PD-L1 endosomal recycling and lysosomal degradation via engineered exosome-based nanocomposites overcomes immune resistance in lung cancer brain metastasis

Abstract

While anti-PD-L1 antibody (αPD-L1) therapy holds promise, its efficacy against lung cancer brain metastasis (LCBM) is severely limited by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment and adaptive immune resistance. To overcome these barriers, we engineered a pH-responsive nanocomposite (VP-αPD-L1@REB) by functionalizing brain-metastatic tumor cell-derived exosomes (EB) with RGD peptides (REB) for targeted co-delivery of verteporfin (VP) and αPD-L1. Benefiting from homotypic affinity and integrin-mediated transcytosis, VP-αPD-L1@REB efficiently crosses the BBB, accumulates within intracranial tumors, and undergoes pH-responsive cargo release. Mechanistically, VP induces a lethal reactive oxygen species (ROS) storm for direct tumor ablation. Simultaneously, VP downregulates the chaperone protein CMTM6 and activates cellular autophagy, forcibly driving internalized PD-L1 toward degradation via dual “endosome-lysosome” and “autophagy-lysosome” pathways. Driven by the synergy of VP's robust intracellular clearance and αPD-L1's surface blockade, this targeted nanoplatform successfully remodels the intracranial immunosuppressive microenvironment and triggers potent systemic anti-tumor immunity. This study provides a highly promising translational paradigm for overcoming adaptive immune resistance in central nervous system (CNS) malignancies.