Antibody–Drug Conjugates Targeting Resistance-Associated Signaling Pathways: Recent Advances and Future Perspectives

Antibody-drug conjugates (ADCs) represent a paradigm shift in precision oncology, ingeniously coupling the targeting capability of monoclonal antibodies with the lethal potency of cytotoxic payloads to selectively eradicate tumor cells. While ADCs have demonstrated transformative efficacy across a spectrum of malignancies, the emergence of intrinsic and acquired resistance remains a formidable obstacle, frequently culminating in treatment failure and disease progression. The landscape of ADC resistance is highly complex, governed by a diverse array of molecular mechanisms. These range from alterations in antigen dynamics-such as downregulation or impaired trafficking-to intracellular adaptations, including the upregulation of multi-drug resistance efflux pumps, enhanced DNA damage repair capacity, and the blockade of apoptotic cell death. Moreover, tumor cells often exploit compensatory signaling networks to bypass therapeutic inhibition. Consequently, elucidating the intricate signaling cascades that drive these resistance phenotypes is critical for clinical advancement. This review comprehensively examines the pivotal signaling pathways underpinning ADC resistance and evaluates novel therapeutic strategies designed to circumvent these molecular barriers, aiming to optimize patient outcomes.