Development of Oncolytic Virus-Proteolysis-Targeting Chimera Conjugates for Tumor Immunotherapy.

The development of proteolysis-targeting chimeras (PROTACs) represents a promising strategy for targeted protein degradation in cancer therapy. However, the limited tumor-specific targeting and the inherent unfavorable physicochemical properties of PROTACs lead to insufficient cellular uptake and suboptimal antitumor immune responses. Herein, as a proof of concept, we developed an oncolytic virus-PROTAC conjugate (BPAD) by efficiently coupling bromodomain-containing protein 4 (BRD4)-targeting PROTACs with oncolytic viruses (OVs). In BPAD, the potent and highly selective infection of OVs to tumor cells enhances both cellular uptake and tumor-selective delivery of PROTACs, resulting in a 640-fold increase in the protein degradation efficiency. Moreover, prior to OV-induced tumor lysis, the preferential replication of OVs within tumor cells, combined with BRD4 degradation, promotes the secretion of type I interferons and facilitates dendritic cell maturation. Overall, the BPAD strategy enables the development of biologically derived macromolecular PROTAC conjugates, thereby enhancing the clinical translation potential of diverse PROTACs.