UNC5D (unc-5 netrin receptor D) is a multifunctional guidance receptor and tumor suppressor with critical roles in neural development and cancer biology. As a netrin receptor, UNC5D mediates axon guidance and cell migration during neural development through interaction with GPC3, forming octameric complexes that guide pyramidal neuron migration and regulate cell guidance via glycan-mediated mechanisms 1. UNC5D functions as a dependence receptor promoting neuronal survival when bound to netrin ligands and mediates cell-cell adhesion through FLRT protein interactions 2. The receptor regulates apoptosis via p53-dependent mechanisms, acting as a direct p53 transcriptional target that induces apoptosis in response to DNA damage 3. Clinically, UNC5D exhibits tumor-suppressive properties frequently lost in multiple cancers. In renal cell carcinoma, colorectal cancer, and prostate cancer, UNC5D expression is downregulated through promoter hypermethylation (40.9-99.7% of cases) and loss of heterozygosity 4, 5, 6. Restoration of UNC5D inhibits cell proliferation, migration, and invasion while inducing G2-M cell-cycle arrest 5. Additionally, UNC5D genetic variants modify susceptibility to environmental neurotoxicity 7, and UNC5D inhibition impairs glucose-stimulated insulin secretion in pancreatic β-cells 8, suggesting broader metabolic functions. These findings establish UNC5D as a tumor suppressor with potential therapeutic and biomarker applications.