Antibody-drug conjugates in breast cancer: current resistance mechanisms and future combination strategies

Antibody-drug conjugates (ADCs), inspired by Paul Ehrlich’s “magic bullet” concept to target cancer cells with cytotoxic drugs while sparing healthy cells, represent a transformative approach in breast cancer therapy. From early agents (e.g., gemtuzumab ozogamicin) to second-generation trastuzumab emtansine (T-DM1) and third-generation trastuzumab deruxtecan (T-DXd)/disitamab vedotin (RC48), ADCs have demonstrated significant clinical benefits, including improved progression-free survival (PFS) and overall survival (OS) in breast cancer, with several approved for clinical use. Ongoing preclinical and clinical studies are rigorously exploring ADC combinations with molecular targeted agents, chemotherapy, and immunotherapy. However, de novo and acquired resistance remains a critical barrier to maximizing therapeutic efficacy. This review summarizes ADC mechanisms and clinical outcomes in breast cancer, explores resistance mechanisms, and dissects the biological rationale for combination strategies, aiming to identify novel payloads that enhance patient outcomes.