Structural and functional insights into netrin-1 receptor binding: Therapeutic implications and clinical applications in cancer

Netrin, also known as the 'neuronal guidance molecule', plays a critical role in nervous system development. Netrin-1 has been extensively implicated in the regulation of tumor cell migration, apoptosis, angiogenesis, and epithelial–mesenchymal transition, influencing cancer progression and therapeutic outcomes. As a secreted protein, the biological functions of netrin-1 depend on the formation of complexes with its receptors. This review systematically summarizes the spatial structural features of the netrin-1 receptors UNC5A-D, DCC, NEO1, and integrin family members, along with the detailed crystal structures of their complexes with netrin-1. These receptors predominantly belong to the immunoglobulin superfamily or contain immunoglobulin-like domains and most function as dependence receptors. They primarily recognize and bind to specific domains of netrin-1 through immunoglobulin or fibronectin type III domains, forming oligomerized signaling complexes. Although monoclonal antibodies targeting netrin-1 have demonstrated therapeutic potential in clinical trials and applications as drug delivery vehicles, the development of small-molecule inhibitors targeting the netrin-1 receptor interaction interfaces remains underexplored, and receptor-targeting therapeutics warrant urgent investigation. Therefore, further research on the critical residue networks and structure-activity relationships at the netrin-1 receptor complex interfaces are needed to elucidate the precise structural mechanisms and develop innovative targeting approaches.