Overcoming resistance to antibody-drug conjugates: mechanisms and emerging strategies

BACKGROUND: Antibody-drug conjugates (ADCs) combine a tumor antigen-specific monoclonal antibody with a cytotoxic payload via a linker, enabling 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. METHODS: In this review, we summarize and analyze molecular pathways implicated in ADC resistance across multiple cancer types, including triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, and relapsed/refractory acute myeloid leukemia. We further examine emerging strategies to overcome resistance, with particular emphasis on combination therapies and the development of next-generation ADCs. RESULTS: Accumulating evidence indicates that identifying and targeting key resistance-associated pathways can expand the population of patients who benefit from ADC therapy and extend the therapeutic lifespan of these agents. We highlight representative preclinical studies that have elucidated resistance mechanisms and demonstrate potential approaches to restore or enhance ADC efficacy. CONCLUSION: Understanding and overcoming ADC resistance is essential as these agents continue to expand into new therapeutic settings. By bridging basic mechanistic insights with translational and preclinical evidence, this review provides a comprehensive framework for addressing ADC resistance and informs future strategies for optimizing cancer treatment.