A DNA-Mediated Lysosomal Degradation Strategy for Targeted Degradation of PD-L1 Protein.

The expression of programmed cell death ligand 1 (PD-L1) enables tumor cells to evade immune surveillance by T-cells. The level of PD-L1 on the cell surface plays a crucial role in the effectiveness of PD-L1-targeted immune checkpoint blockade therapy. Therefore, we utilized the unique trafficking capabilities of scavenger receptors (SRs) to direct PD-L1 to lysosomes for degradation. By employing click chemistry to conjugate the PD-L1 inhibitor BMS-202 with dendritic DNA scaffolds, we created a bifunctional compound, PBL1, which is capable of simultaneously targeting both SRs and PD-L1. PBL1 effectively induces PD-L1 degradation both in vitro and in vivo, significantly reducing the off-target toxicity commonly associated with traditional PD-L1 inhibitors. The efficacy and specificity of PBL1 have been validated in A549 cells and zebrafish models. The development of this SRs-mediated lysosomal degradation strategy offers a promising new approach for cancer immunotherapy, providing a safer and more targeted alternative to existing PD-L1 inhibitors.