New research flagged a specific “target-high but uptake-defective” state that can drive resistance to ADCs, with attention centered on Padcev (enfortumab vedotin). The work suggests that beyond target expression, efficient internalization and cell uptake can be decisive for ADC effectiveness, reframing how resistance may emerge even when surface antigens are abundant. The findings, reported by separate teams, imply that future ADC development and companion biomarker strategies may need to account for uptake competence, not just antigen levels. For drug developers, this can influence selection of targets, linker/antibody pairing, and patient stratification. A major practical question now is whether targeting uptake pathways or adjusting conjugate properties can overcome or prevent this resistance phenotype in later-line settings.