Development of Oncolytic Virus-Proteolysis-Targeting Chimera Conjugates for Tumor Immunotherapy
Zhixiong Gao, Hanwei Huang, Ying Zhi, Hu Wu, Yongcheng Guo, Yanhao Dong, Yuhang Du, Zao Ji, Shihua Yang, Yaohe Wang, Zhenguo Cheng, Huiling Gao, Xinyi Jiang, Min Jiang, Kun Zhao, Funan LiuAbstract
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.