Molecular and immune-mediated resistance to antibody-drug conjugates in breast cancer

Abstract

Antibody-drug conjugates (ADCs) have progressively advanced the conceptual framework of targeted oncology, evolving from a way to deliver chemotherapy selectively to tumor cells into drugs that also interact with the immune system to support their action. In breast cancer, the approval of several novel ADCs has transformed the therapeutic landscape across HER2-positive, HER2-low and triple-negative disease. Despite these advances, primary and acquired resistance remain the dominant clinical challenge. This narrative review classifies these resistance mechanisms, examining their interactions and therapeutic implications. We organize resistance along two highly interconnected domains. A molecular domain encompasses target antigen alterations, defective endolysosomal trafficking, payload efflux, and altered apoptotic thresholds. An immunological domain includes impaired Fc-mediated functions, escape from immunogenic cell death, and microenvironment-mediated immunosuppression. These domains frequently converge each other to drive clinical failure. Importantly, immune-mediated effects depend heavily on specific ADC constructs, and their clinical impact requires further validation. While routine assays currently assess baseline candidate markers, advancing rational therapeutic sequencing will require validated biomarkers capable of capturing dynamic processes, such as receptor trafficking or functional immune evasion.