Minji Seo, Jangsoon Lee, Naoto T. Ueno
Antibody-drug conjugates (ADCs) have revolutionized the treatment landscape of breast cancer by combining the precision of monoclonal antibodies with the potency of cytotoxic agents. Despite the clinical success of ADCs-with 4 FDA-approved agents to date, and 15 for the entire cancer landscape-their therapeutic durability is frequently undermined by acquired resistance. Rather than arising solely from tumor-intrinsic alterations, ADC resistance reflects a multi-layered process shaped by dynamic interactions among cancer cells and the tumor microenvironment (TME), with activation of adaptive signaling networks. For example, stromal architecture, vascular heterogeneity, and immune modulation intersect with clonal evolution, phenotypic plasticity, and pathway reprogramming, thereby constraining ADC delivery and activity. Cutting-edge technologies such as spatial omics, single-cell profiling, functional genomics, and patient-derived models are redefining how these resistance mechanisms are mapped and understood in situ. Building on these insights, emerging therapeutic strategies aim to overcome resistance through mechanism-guided interventions, including next-generation ADC designs, co-targeting of compensatory signaling pathways, and biomarker-informed therapeutic strategies. Together, these integrated biological and technological perspectives provide a framework for developing more durable and precisely tailored ADC-based therapies in breast cancer.