Degrader-Drug Conjugate (DDC) Mediated Immunochemotherapy for Tumor Treatment

Due to the heterogeneity of tumors and the complex regulatory mechanisms governing PD-L1 expression, immunotherapy that employs PD-1/PD-L1 inhibitors has shown limited efficacy and relatively low response rates. In this work, we propose that a Degrader-Drug Conjugate (DDC), comprising a PD-L1 degrader linked to a cytotoxic agent, may enhance antitumor efficacy by synergizing immune activation with direct cell killing. Mechanistically, the DDC promotes PD-L1 degradation via the endosomal-lysosomal pathway to alleviate immunosuppression, while simultaneously releasing a cytotoxic agent inside tumor cells to induce apoptosis. Among the two DDCs developed in this study, BMS-RGD-MMAE exhibits superior toxin release efficacy, enhanced plasma stability, and increased cytotoxicity compared to BMS-RGD-DXd. Moreover, BMS-RGD-MMAE significantly inhibits tumor growth in vivo through synergistic PD-L1 degradation and toxin-mediated cell death, underscoring its substantial potential for application in tumor immunochemotherapy. Overall, this DDC platform provides new opportunities for the advancement of antitumor therapeutics.