Drug resistance to antibody-drug conjugates: mechanisms, challenges, and perspectives

Antibody-drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics by combining the target precision of antibodies with the potent cytotoxic effects of chemotherapeutic agents. This unique approach aims to enhance the effectiveness of cancer treatment while minimizing systemic toxicity. This review provides a comprehensive overview of ADC development, starting with explorations of the structural and mechanistic foundations, and advancing to in-depth analyses of ADCs that have achieved clinical success. Despite remarkable progress, the development of drug resistance remains a significant barrier to broader clinical application. We discuss the mechanisms underlying resistance, including alterations in target antigens, disruptions in ADC internalization, and dysfunctions of intracellular trafficking. To address these challenges, we propose several strategies, such as designing next-generation ADCs equipped with improved linkers and novel payloads, implementation of combination therapies, and simultaneous targeting of multiple pathways to circumvent resistance. In conclusion, this review highlights the critical need for innovative approaches in the evolving ADC landscape, aiming to overcome resistance mechanisms and fully harness the therapeutic promise of ADCs in cancer treatment.