Innovations in HER2-targeted therapy: A comprehensive review of trastuzumab deruxtecan

Trastuzumab deruxtecan (T-DXd) has emerged as a revolutionary antibody-drug conjugate (ADC) that has shown remarkable clinical efficacy across multiple HER2-expressing tumor types. Comprising a humanized anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor via a cleavable and stable tetrapeptide-based linker, T-DXd integrates the specificity of targeted therapy with the cytotoxic potency of chemotherapy. As the most promising ADC in the era of precision oncology, T-DXd has been approved to treat a series of malignant tumors. However, its widespread clinical application is challenged by treatment-related adverse events, the emergence of drug resistance, and uncertainties in biomarker-guided patient selection. This review provides a comprehensive overview of T-DXd's molecular design, mechanisms of action, and major findings from key clinical trials. It also examines resistance pathways and safety considerations, and discusses strategies to optimize therapeutic outcomes, including rational combination approaches with immune checkpoint inhibitors or other targeted agents. Finally, we explore future directions in T-DXd development, emphasizing the importance of precision medicine, biomarker refinement, and next-generation ADC engineering to further enhance efficacy and safety.