Antibody–drug conjugates in cancer therapy: current landscape, challenges, and future directions
Bonan Chen, Xiaohong Zheng, Jialin Wu, Guoming Chen, Jun Yu, Yi Xu, William Ka Kei Wu, Gary M. Tse, Ka‐Fai To, Wei Kang
Abstract
Antibody-drug conjugates (ADCs) have emerged as a transformative modality in oncology by combining the target specificity of antibodies with the high potency of diverse cytotoxic payloads. This review provides an integrative overview of ADCs, spanning from molecular design to clinical translation. We dissect the structural components, antibodies, linkers, and payloads, and elucidate their impact on pharmacokinetics, tumor selectivity, and therapeutic index. Mechanistic pathways, including antigen recognition, receptor-mediated internalization, payload release, and immunogenic cell death (ICD), are highlighted to provide context for ADC function. Clinically, ADCs have demonstrated efficacy across hematologic and solid malignancies, with 15 Food and Drug Administration (FDA) approvals and an expanding investigational pipeline. However, challenges persist, including antigen heterogeneity, resistance mechanisms, systemic toxicities, and manufacturing complexities. Emerging innovations such as bispecific ADCs, immune-stimulatory payloads, AI-guided design, and nanotechnology-enhanced delivery are reshaping the ADC landscape. Finally, we emphasize the necessity of diagnostic precision and rational combination strategies, while highlighting emerging innovations that collectively shape the future direction of next-generation ADC therapeutics.