Antibody-drug conjugate (ADC) is a drug modality where a payload is conjugated to an antibody for its targeted delivery to the cancer cells. In breast cancer, the treatment landscape has changed remarkably in the past decade by the introduction of several effective ADCs in the clinic. However, intrinsic (de novo) or acquired resistance to these treatments is a major obstacle. In this review, we summarize the role of target antigen alterations, cell-intrinsic mechanisms that overcome payload cytotoxicity, and the pro-tumorigenic tumor microenvironment (TME) as the major drivers of resistance to ADCs. Furthermore, we discuss how different mechanisms of ADC resistance are integrated and highlight the most clinically relevant ones. We then provide the current and emerging strategies, such as biomarker-guided drug combinations and novel ADC designs to overcome resistance to ADCs. Finally, we provide future perspectives on the use of preclinical models that better reflect both intratumor heterogeneity and TME, integration of exploratory biomarker analysis through multi-omics of patient biopsies in prospective clinical trials, and development of new ADCs, e.g., bispecific ADCs and identification of novel antigens and/or payloads, to overcome ADC resistance.

Antibody-drug conjugate (ADC)

Breast cancer

Mechanisms of resistance

Target antigen

Payload

Bystander effect

Tumor immune microenvironment

© 2026 The Authors. Published by Elsevier Ltd.