Overcoming Resistance to Antibody-Drug Conjugates (ADCs): Mechanisms and Emerging Strategies.

Antibody-drug conjugates (ADCs) combine a tumor antigen-specific monoclonal antibody with a cytotoxic payload via a linker, allowing selective delivery of cytotoxic agents to cancer cells while minimizing damage to healthy tissues. This approach has revolutionized cancer treatment. However, despite these advantages, resistance to ADCs has emerged as a significant barrier to long-term efficacy. Understanding and overcoming ADC resistance is crucial, especially for cancers with limited treatment options like triple-negative breast cancer (TNBC), non-small cell lung cancer, pancreatic cancer, and relapsed/refractory acute myeloid leukemia. Moreover, as ADCs expand into new therapeutic areas, overcoming resistance is essential to preserve their effectiveness and explore novel settings, including combination therapies. Identifying molecular pathways involved in ADC resistance and addressing these mechanisms can benefit more patients and extend ADCs' therapeutic lifespan. This review focuses on elucidating these pathways and explores innovative strategies to overcome resistance, including combination therapies and the development of next-generation ADCs. We also highlight key preclinical studies, bridging the gap between basic research and clinical applications, to provide a comprehensive understanding of ADC resistance and its impact on future cancer treatments.