PD-L1-targeted polymer-peptide-immune nanomedicine synergizes radiotherapy for durable tumor control.

Radiotherapy (RT) is a cornerstone of cancer treatment but limited by its dual role in modulating the tumor immune microenvironment: while promoting immunogenic cell death (ICD), RT concurrently upregulates PD-L1 to suppress antitumor immunity. To address this limitation, we developed PEP-PLG-IMDQ, a polymer-peptide-immune agonist nanomedicine that synergizes RT with immunotherapy. This nanoplatform employs a poly (-glutamic acid) carrier conjugated with a PD-L1-targeting peptide and the TLR7/8 agonist imidazoquinoline (IMDQ), enabling three-pronged action: (1) PD-L1-mediated tumor targeting, (2) TLR7/8-driven dendritic cell activation, and (3) reinforcement of the anti-tumor immune cycle. In CT26 tumor-bearing mice, RT combined with PEP-PLG-IMDQ achieved 98.1 % tumor suppression, with 83 % long-term survival and complete resistance to tumor rechallenge. Mechanistically, the combination therapy enhanced CD8 T cell infiltration (5.3-fold vs. RT alone) and established durable immune memory. Our work provides a translatable strategy to overcome radioresistance through spatiotemporal immune modulation.