Overcoming resistance to antibody-drug conjugates: from mechanistic insights to cutting-edge strategies

Abstract Antibody-drug conjugates (ADCs) have revolutionized cancer therapy, but therapeutic resistance poses a significant barrier to sustained efficacy. Multiple mechanisms contribute to ADCs resistance, including drug efflux mediated by transporters, alterations in target antigens, tumor heterogeneity, and the impact of the tumor microenvironment (TME). Clinically, ADCs resistance varies across different cancer types, treatment lines, and patient subgroups. Emerging strategies now emphasize precision targeting through bispecific ADCs, alongside advancements in linker chemistry, payload design, and TME modulation. Additionally, rational combination therapies have emerged as a promising approach to reverse ADCs resistance, demonstrating synergistic effects. This review summarizes current understanding of mechanisms driving ADCs resistance and recent advances in combination therapies. By integrating mechanistic insights with emerging strategies, we aim to provide a comprehensive framework for addressing ADCs resistance and propose future research directions. These efforts may improve the efficacy of ADCs and the outcomes of cancer patients.