UNC5B (unc-5 netrin receptor B) is a multifunctional netrin receptor with critical roles in neural development, vascular biology, and cell fate determination. Primarily, UNC5B mediates axon guidance through netrin-1 binding, enabling axon repulsion in developing neuronal growth cones 1. In vascular contexts, UNC5B negatively regulates angiogenesis by mediating retraction of endothelial tip cell filopodia in response to netrin-1 2. A key mechanistic feature is UNC5B's dependence receptor function: in the absence of netrin-1 ligand, UNC5B induces apoptosis through DAPK1 activation, while netrin-1 binding suppresses this pro-apoptotic signal 2. UNC5B-Δ8, an endothelial-specific splicing isoform, constitutively promotes apoptosis independent of netrin-1 and is essential for proper vascular development 2. Beyond development, UNC5B is implicated in epithelial-to-mesenchymal transition (EMT) in cancer; netrin-1 blockade via anti-UNC5B approaches reduces EMT progression and enhances chemotherapy sensitivity 3. In glioblastoma, UNC5B activation promotes neural differentiation and suppresses cancer cell proliferation 4. Clinically, UNC5B dysregulation associates with poor outcomes in colon cancer and osteosarcoma through lncRNA-mediated mechanisms 56. Additionally, UNC5B cooperates with Neo1 to regulate pluripotency in embryonic stem cells via Wnt and MAPK pathway modulation 1, and marks pancreatic islet endothelial cells with distinct metabolic and angiocrine functions 7.