Researchers published findings identifying a potential ADC resistance mechanism described as a “target-high but uptake-defective” state, drawing attention to how internalization defects can limit antibody-drug conjugate efficacy. The work focused on resistance to Padcev (enfortumab vedotin) and explored whether similar biology may contribute to broader ADC failure modes. The studies add a layer to the ADC resistance playbook by shifting some emphasis from target abundance alone to the downstream ability of tumors to internalize and process ADC-bound drug payloads. Investigators also suggested this state may help explain why some target-positive tumors do not respond durably. With ADCs remaining a dominant precision oncology modality, these mechanistic insights could influence next-generation design choices and patient selection strategies.