Integrating PD-L1-targeted radioligand with protein degradation for precision tumor theranostics

Targeting programmed death ligand 1 (PD-L1) with proteolysis-targeting chimera (PROTAC) remains challenging due to the inability of visualized synergistic methods. Here, we report an integrated PD-L1-Targeted Radioligand with Protein Degradation (PRPD) platform that synergistically merges positron emission tomography (PET) imaging, targeted protein degradation, radiostimulation and radioligand therapy into a single small-molecule construct. We developed this radiotheranostic platform by designing amino acid-based linkers to conjugate PD-L1-targeting moiety, E3 ubiquitin ligase ligand, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. PET imaging enabled visualization of PD-L1 biodistribution, transforming degrader dosing from an empirical "black box" into an image-guided intervention. [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-BLP showed specific, time-dependent tumor uptake in MC38-bearing mice, which was blocked by BMS1166. Mechanistically, the radioligand induced DNA damage and upregulated PD-L1 expression, thereby "priming" the tumor for enhanced targeted degradation. Combining a single 7.4 MBq dose of [¹⁷⁷Lu]Lu-DOTA-BLP with DOTA-BLP significantly enhanced tumor suppression and survival versus monotherapy, with minimal toxicity. Collectively, this work established a PRPD strategy that provides a visual, synergistic, and precision-guided approach for dynamic protein degradation in immuno-oncology.