Resistance to antibody-drug conjugates in breast cancer: mechanism and strategies for overcoming

Antibody-drug conjugates (ADCs) have profoundly reshaped the treatment landscape of breast cancer, demonstrating definite survival benefits especially in HER2-positive and HER2-low advanced breast cancer. However, their widespread clinical application has also made primary resistance, acquired resistance, and cross-resistance increasingly prominent. Drug resistance has become a critical bottleneck in achieving long-term survival benefits for breast cancer patients. The multidimensional molecular mechanismsof ADC resistance in breast cancer include: First, downregulation of tumorassociated antigen expression, altered spatial heterogeneity, and antigen gene mutations can weaken the binding of ADCs to tumor cells; Second, aberrant expression and function of endocytic receptors and related proteins, as well as impaired lysosomal function, can lead to defects in ADC internalization and trafficking; Third, upregulation of drug efflux pumps, enhanced DNA repair, and topoisomerase I mutations are key factors underlying payload resistance; Fourth, abnormal activation of classical signaling pathways such as PI3K/AKT/mTOR and MAPKcan promote tumor cell survival; Fifth, immunosuppressive microenvironment components such as tumor associated macrophages and fibroblasts also play important roles in ADC resistance. Stepwise strategies for overcoming ADC resistance in breast cancer include: First, developing “next-generation ADCs” with novel targets, innovative payloads, and cleavable linkers; Second, combining existing ADCs with agents such as immune checkpoint inhibitors and irreversible tyrosine kinase inhibitors to achieve synergistic efficacy and reverse resistance, among which ADCs combined with immune checkpoint inhibitors has shown the most promising clinical prospects; Third, leveraging organoid technology and artificial intelligence(AI) platforms to enable precision personalized medication design and development. Although clinical validation of combination regimens and translation of novel drugs still require considerable time, in-depth analysis of the drug-resistant tumor microenvironment and its heterogeneity by multi-technology integration may provide direction for breaking the efficacy bottleneck of ADCs and achieving precision individualized treatment for breast cancer. In the future, integrating microenvironmental feature profiling with AI-driven drug development and clinical translation of organoid technology is expected to provide critical support for overcoming the bottleneck of ADC resistance, thereby driving substantial progress in the treatment landscape of breast cancer.