Next-generation antibody–drug conjugates in drug-resistant solid tumors: promise, toxicity, and the emerging challenge of acquired resistance

Drug-resistant solid tumors represent a major challenge in oncology, with resistance mechanisms, including efflux pump overexpression, apoptotic pathway alterations, and adaptive survival signaling, contributing to poor outcomes despite multimodal therapy. Conventional chemotherapy and first-generation antibody–drug conjugates (ADCs), such as ado-trastuzumab emtansine (T-DM1), were limited by non-specific cytotoxicity, heterogeneous drug–antibody ratios, linker instability, and insufficient bystander killing, yielding modest efficacy in heavily pretreated populations. Next-generation ADCs address these shortcomings through site-specific conjugation, advanced cleavable linkers, and novel payloads, such as topoisomerase I inhibitors, enabling robust bystander killing and circumvention of efflux-mediated resistance. Clinically, trastuzumab deruxtecan demonstrated meaningful progression-free survival benefit in HER2-low metastatic breast cancer, while enfortumab vedotin reduced mortality risk in platinum- and immunotherapy-refractory urothelial carcinoma, establishing ADC efficacy across solid tumor histologies. However, significant toxicity concerns persist. Trastuzumab deruxtecan carries a 15.4% incidence of interstitial lung disease, including fatal events, and sacituzumab govitecan is associated with grade 3 or higher neutropenia in approximately 51% of patients. Furthermore, next-generation ADCs are not resistance-proof, with antigen downregulation, payload efflux, and impaired internalization emerging as clinically relevant escape mechanisms. Biomarker-driven patient selection, rigorous toxicity monitoring, and prospective trials addressing resistance will be essential to realizing the full and durable potential of this drug class.