Antibody-Drug Conjugates Powered by Deruxtecan: Innovations and Challenges in Oncology

Antibody-drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), and trophoblast cell surface anti-gen 2 (TROP2), including breast, lung, gastric, and other solid tumors. DXd, a potent topoisomerase I inhibitor, enhances the cytotoxic potential of ADCs through a cleava-ble and stable linker and a high drug-to-antibody ratio that ensures optimal drug re-lease. The clinical success of trastuzumab DXd (Enhertu®) and datopotamab DXd (Datroway®), along with the ongoing development of patritumab DXd, has expanded the therapeutic potential of ADCs. However, challenges remain, including toxicity, re-sistance, and manufacturing scalability. This review discusses the mechanisms of ac-tion, clinical progress, and challenges of DXd-based ADCs, highlighting their trans-formative role in modern oncology and exploring future directions to optimize their efficacy and accessibility.