Nectins mediate cell–cell adhesion via extracellular immunoglobulin-like domains. Among them, Nectin-4 is an established therapeutic target in several cancers, most notably urothelial carcinoma, where antibody–drug conjugates such as Enfortumab Vedotin (EV) bind to Nectin-4 and induce selective tumor cell death through intracellular release of a cytotoxic payload 1 . Beyond Antibody-drug conjugates (ADCs), Nectin-4 is being investigated as a target in additional therapeutic strategies, including oncolytic measles viruses that selectively infect and lyse Nectin-4–positive tumor cells 2 , as well as immunotherapeutic approaches using cytotoxic T lymphocytes directed against Nectin-4 3 . Nectin-4 also serves as a ligand for the immune checkpoint TIGIT, and its blockade may modulate T-cell and NK-cell activity 4 . Furthermore, Nectin-4–targeting CAR-T cells have demonstrated antitumor activity in preclinical models 5 . Despite these advances, Nectin-4 has received little attention in renal cell carcinoma (RCC). This study aims to characterize Nectin-4 expression in normal renal tissue, primary tumors, and metastases of clear cell RCC (ccRCC), and to evaluate its association with clinicopathological features and overall survival (OS). Ultimately, we address whether Nectin-4 expression in ccRCC supports its potential as a therapeutic target, including for ADC-based approaches.
Klein et al. (2026) studied this question.