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

Sep 23, 2026

Gu et al. develop ASA, an antibody-PROTAC conjugate for triple-negative breast cancer that combines tumor targeting, hypoxia-responsive linker cleavage, and PROTAC-mediated degradation. The design promotes intratumoral degradation and strengthens antitumor immunity, generating robust long-term immune memory. Compared with PROTAC alone, ASA shows enhanced targeting and efficacy. When combined with anti-PD-L1, ASA improves tumor control and boosts CD8+ T cell responses, supporting durable therapeutic potential.

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Article An antibody-PROTAC conjugate targets BRD4/cMyc/PD-L1 to enhance immunotherapy efficacy in triple-negative breast cancer Authors Yunru Gu, Chen Li, Yuhan Zhao, , Jiaxuan Chen, Jinbo Li, Xiaoxiang Guan Correspondence [jinboli@nju.edu.cn](jinboli@nju.edu.cn) (J.L.), [xguan@njmu.edu.cn](xguan@njmu.edu.cn) (X.G.) In brief Gu et al. develop ASA, an antibodyPROTAC conjugate for TNBC, that integrates tumor homing, hypoxiaresponsive cleavage, and PROTACmediated degradation. This design enables targeted degradation within tumors and promotes robust antitumor immunity and long-term immune memory when combined with αPD-L1 . • ASA exhibits enhanced targeting and efficacy compared with PROTAC alone • ASA plus αPD-L1 improves tumor control and CD8+ T cell responses Gu et al., 2026, Cell Reports Medicine 7, 102948 August 18, 2026 © 2026 The Author(s) . Published by Elsevier Inc. [https://doi.org/10.1016/j.xcrm.2026.102948](https://doi.org/10.1016/j.xcrm.2026.102948) ll ll OPEN ACCESS Article An antibody-PROTAC conjugate targets BRD4/c-Myc/PD-L1 to enhance immunotherapy efficacy in triple-negative breast cancer Yunru Gu,1,5 Chen Li,2,5 Yuhan Zhao,1,5 Tianrui Xu,1 Ye Zhu,1 Dandan Wang,3 Xiaoning Wang,2 Jiaxuan Chen,1 Jinbo Li,2,* and Xiaoxiang Guan1,4,6,* 1Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China 2State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023, China 3Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China 4Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China 5These authors contributed equally 6Lead contact *Correspondence: [jinboli@nju.edu.cn](jinboli@nju.edu.cn) (J. L.), [xguan@njmu.edu.cn](xguan@njmu.edu.cn) (X.G.) [https://doi.org/10.1016/j.xcrm.2026.102948](https://doi.org/10.1016/j.xcrm.2026.102948) SUMMARY 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 inTNBC is hindered by inefficient delivery. Here, we develop ASA, aTNBC-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-L1to 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. INTRODUCTION Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a poor long-term prognosis.1 Due to its absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2, which are key targets for conventional breast cancer therapies, TNBC has long faced a targeted treatment dilemma.2 In recent years, modalities including immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and inhibitors targeting oncogenic vulnerabilities have been success

FAQs

What is ASA and what does it target in triple-negative breast cancer?

ASA is an antibody-PROTAC conjugate designed for TNBC. It targets BRD4 for degradation and involves suppressing downstream c-Myc and PD-L1 pathways.

Why is hypoxia-responsiveness important for ASA?

ASA uses a hypoxia-triggered linker cleavage mechanism, enabling more effective activation and targeted protein degradation within tumors under hypoxic conditions.

How does combining ASA with anti-PD-L1 affect treatment outcomes?

Anti-PD-L1 amplifies ASA’s effects on tumor control and enhances CD8+ T cell infiltration and activation, leading to stronger and more durable immunity.

Sep 23, 2026

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