Antibody-drug conjugates in breast cancer: From therapeutic and immune activation mechanisms to resistance prevention

Antibody-drug conjugates (ADCs) are produced by integrating the specificity of monoclonal antibodies with cytotoxic payloads. ADCs are vital biologics for breast cancer treatment where they not only exert direct cytotoxicity but also promote anti-tumor immune responses against breast cancers. In this review, the structure, mechanism of action, and the anti-tumor immune response properties of approved and emerging ADCs are presented and discussed. The FDA-approved ADCs include trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG-Trop2), and trastuzumab deruxtecan (T-DXd), as well as two emerging ADCs, i.e. datopotamab deruxtecan (Dato-DXd) and ladiratuzumab vedotin (LV). Preclinical and clinical studies demonstrate their efficacy in multiple breast cancer subtypes (e.g. HER2⁺ and triple negative breast cancers). These ADCs exert anti-tumor activity through cytotoxic effects and immune responses primarily by recruiting and activating cytotoxic T cells. Moreover, combining ADCs with immune checkpoint inhibitors (ICIs) shows enhanced therapeutic outcomes. ADCs resistance is caused by heterogeneous target antigens expression, modified ADC processing including endocytosis and lysosomal trafficking, as well as upregulated drug-efflux pumps that decrease payload concentration intracellularly. Strategies to mitigate ADCs resistance include multi-target ADCs, and stability-enhancing linkers that also reduce off-target toxicities. ADCs continue to play key roles in breast cancer treatment, while next-generation ADCs may address current ADCs' limitations and resistance mechanisms.