Nectin-4, Bladder Cancer, and Nuclear Medicine: A Theranostic Frontier

Bladder cancer is among the top ten most common cancers globally, with advanced or metastatic disease associated with dismal survival outcomes. Current diagnostic imaging and therapies have significant limitations, highlighting the urgent need for novel theranostic targets. Nectin-4, a cell adhesion molecule frequently overexpressed in bladder cancer, especially urothelial carcinoma (∼60%-87% of tumors), has emerged as a promising biomarker and therapeutic target. This review critically evaluates the role of Nectin-4 in bladder cancer and explores its exciting potential in nuclear medicine for combined molecular imaging and targeted radionuclide therapy-embracing the "theranostic" paradigm. Nectin-4 is abundantly and selectively expressed in most urothelial carcinomas, correlating with advanced disease and poorer prognosis. Clinically validated by the FDA-approved antibody-drug conjugate enfortumab vedotin, Nectin-4 targeting achieves objective response rates around 40%-50% and significantly improves survival in refractory advanced urothelial carcinoma. Recent clinical advances in Nectin-4-targeted PET imaging (such as ⁶⁸Ga-labeled agents) have demonstrated excellent tumor localization and specificity, enabling precise patient selection for targeted therapies. Additionally, emerging radionuclide therapeutics (eg, ²²⁵Ac- and ¹⁷⁷Lu-based agents) show promising preclinical and early clinical efficacy, robust tumor targeting, and favorable safety profiles. Targeting Nectin-4 represents a new frontier in the management of bladder cancer, bridging the gap between precise molecular diagnostics and personalized targeted radionuclide therapy. Ongoing clinical trials and translational research are rapidly advancing this promising theranostic strategy towards routine clinical application, with significant potential to enhance patient selection, treatment monitoring, and ultimately, clinical outcomes.