Synergism of Cu-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect.

We put forward a novel targeting-triggering-therapy (TTT) scheme that combines Cu-based targeted radionuclide therapy (TRT) with programmed death-ligand 1 (PD-L1)-based immunotherapy for enhancing therapeutic efficacy. The αβ integrin-targeted Cu-DOTA-EB-cRGDfK (Cu-DER) was synthesized. Flow cytometry, immunofluorescence staining, and RT-qPCR were performed to verify PD-L1 upregulation after irradiation with Cu-DER. Positron emission tomography imaging was performed to investigate the prominent tumor retention property of Cu-DER. In the MC38 tumor model, anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner after Cu-DER was injected, followed by the testing of changes in tumor microenvironment (TME). PD-L1 was upregulated in a time- and dose-dependent manner after being induced by Cu-DER. The combination of Cu-DER TRT (925 MBq/kg) and αPD-L1 mAb (10 mg/kg) resulted in significant delay in tumor growth and protected against tumor rechallenge. Blockade of PD-L1 at 4 h after Cu-DER TRT (Cu-DER + αPD-L1 mAb @ 4 h combination group) was able to achieve 100% survival rate, prevent tumor relapse, and evidently prolong the survival of mice. In summary, the combination of Cu-DER and αPD-L1 mAb in a time-dependent manner could be a promising approach to improve therapeutic efficacy. Understandably, this strategy has the potential to extend the scope of Cu-based TTT and merits translation into clinical practice for the better management of immune checkpoint blockade immunotherapy.