Mechanisms of resistance to antibody-drug conjugates in cancer therapy: molecular basis and therapeutic strategies

Antibody-drug conjugates (ADCs) have emerged as a transformative class in oncology, integrating the target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads. By harnessing tumor-specific antigen recognition, ADCs enable the selective delivery of chemotherapeutic agents, thereby enhancing therapeutic efficacy while reducing systemic toxicity. Their clinical success across both hematologic malignancies and solid tumors underscores their potential to redefine targeted cancer therapy. However, the clinical durability of ADCs is increasingly undermined by the emergence of diverse resistance mechanisms that diminish their antitumor activity. These mechanisms encompass the entire drug delivery cascade - from reduced or heterogeneous antigen expression and impaired internalization to defective lysosomal trafficking, enhanced drug efflux, and payload detoxification. In addition, adaptive reprogramming of oncogenic signaling pathways and tumor microenvironmental factors can further attenuate ADC cytotoxicity and promote tumor persistence. A comprehensive understanding of the molecular and cellular bases of ADC resistance is essential for sustaining their therapeutic impact. Advances in linker chemistry, innovative payload design, and the development of bispecific or immune-modulating ADCs offer promising strategies to overcome these challenges. Concurrently, the integration of biomarker-driven patient selection and rational combination regimens is poised to enhance treatment precision and delay resistance. Continued mechanistic and translational research will be pivotal to fully realizing the potential of next-generation ADCs in precision oncology.