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.