Focusing on toxicity management: Challenges and strategies for HER2-targeted antibody–drug conjugates in breast cancer

Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) have revolutionized the treatment landscape of HER2-positive breast cancer, significantly improving patient survival. However, their growing clinical application has revealed a spectrum of serious adverse events (AEs) that can compromise quality of life, reduce treatment compliance, and, in some cases, lead to life-threatening outcomes or premature therapy discontinuation. This review provides a comprehensive overview of the toxicity profiles and underlying mechanisms of HER2-targeted ADCs, with a focus on representative agents such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). We examine the pathogenesis of common toxicities, including thrombocytopenia, interstitial lung disease, cardiotoxicity, and hepatotoxicity, and summarize clinical evidence for monitoring and intervention strategies. Emphasis is placed on the importance of early identification and standardized management to mitigate risk. Furthermore, we discuss emerging approaches to improve ADC safety through structural optimization, including advances in antibody engineering, linker design, and payload selection. This review aims to guide clinicians and researchers in improving the safety and clinical utility of HER2-targeted ADCs in breast cancer treatment.