Nectin-4–Targeted Radiotheranostics for Personalized Cancer Therapy: A Systematic Review

Molecularly targeted therapies are increasingly relevant in clinical oncology, as they enable the selective modulation of specific biologic targets-such as enzymes or receptors-by inhibiting or enhancing their function. Nectin cell adhesion molecule 4 (nectin-4), a tumor-associated antigen, is overexpressed in various malignancies and has been linked to tumor progression and poor clinical outcomes. Its role has recently gained significant attention, particularly in urothelial carcinoma, where nectin-4-targeted antibody-drug conjugates have demonstrated promising therapeutic efficacy. These findings have positioned nectin-4 not only as a relevant target for noninvasive tumor characterization and cancer therapy but also as a valuable biomarker for molecular imaging. This review provides an overview of the recent developments in nectin-4-directed molecular theranostics, on the basis of a literature analysis, with a focus on the design, preclinical validation, and clinical translation of novel radiotracers in nuclear medicine. Multiple nectin-4-targeted radiotracers-comprising antibody- and peptide-based agents-have demonstrated high specificity and strong affinity for nectin-4-overexpressing tumors, particularly in urothelial carcinoma and triple-negative breast cancer. Exploratory preclinical and clinical data consistently showed comparable diagnostic accuracy to standard molecular imaging methods (e.g., [¹⁸F]FDG-based PET), enhanced detection of metastatic lesions, and effective monitoring of therapeutic response and eventual treatment resistance to nectin-4-targeted antibody-drug conjugates.