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Nectin cell adhesion molecule 4 (NECTIN4) is a calcium-independent type I transmembrane protein that mediates cell-cell junction formation through homophilic and heterophilic interactions. It consists of three extracellular immunoglobulin-like domains and a cytoplasmic tail that interacts with Afadin to regulate actin cytoskeleton remodeling and cell migration. NECTIN4 is highly overexpressed in various malignancies, including breast, lung, urothelial, and ovarian cancers, where it promotes tumor growth, angiogenesis, and metastasis via the PI3K/AKT signaling pathway. Under hypoxic conditions, a soluble form of NECTIN4 is shed and interacts with integrin-β4 on endothelial cells to further enhance angiogenesis. Additionally, its intracellular region can translocate to the nucleus to facilitate DNA repair. Clinically, elevated NECTIN4 expression is a well-established biomarker for poor prognosis and reduced survival across multiple cancer types.

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