An antibody-PROTAC conjugate targets BRD4/c-Myc/PD-L1 to enhance immunotherapy efficacy in triple-negative breast cancer.

Abstract

Triple-negative breast cancer (TNBC) remains an aggressive malignancy lacking effective and safe treatments. Proteolysis-targeting chimeras (PROTACs) represent a promising modality for intractable diseases, but their application in TNBC is hindered by inefficient delivery. Here, we develop ASA, a TNBC-targeting antibody-PROTAC conjugate that links a TROP2-specific antibody to a BRD4-degrading PROTAC, with specificity conferred by TROP2-dependent endocytosis and hypoxia-triggered linker cleavage. ASA exhibits superior TNBC targeting and antitumor efficacy compared with its unconjugated PROTAC moiety. ASA monotherapy elicits stronger long-term immunological memory than the antibody-drug conjugate (ADC) sacituzumab govitecan, an effect that is further amplified by anti-PD-L1 combination. Mechanistically, ASA induces sustained BRD4 degradation, suppressing c-Myc and PD-L1 to inhibit tumor progression and drive long-lasting immunity. By disrupting DNA repair pathways, ASA synergizes with anti-PD-L1 to enhance tumor control and increase CD8⁺ T cell infiltration and activation. These findings position ASA as a promising strategy for safe, effective, and durable TNBC therapy.