SEMA6D (semaphorin 6D) is a transmembrane guidance molecule with pleiotropic functions spanning neurodevelopment, immunity, and tissue homeostasis. Primarily, SEMA6D exhibits growth cone collapsing activity on dorsal root ganglion neurons and functions as a chemorepellent in axon guidance 1. Beyond neuronal development, SEMA6D serves as a ligand for TREM2 on dendritic cells and microglia, regulating immune responses and synaptic homeostasis 2. In the tumor microenvironment, SEMA6D forward signaling impairs CD8+ T cell infiltration and activation through plexin-A4, reducing immunotherapy efficacy; blocking SEMA6D restores PD-1 checkpoint inhibitor responsiveness in head and neck cancers 3. SEMA6D in amygdalar interneurons maintains synaptic maturation and γ-aminobutyric acid transmission, coordinating anxiety, metabolic, and inflammatory outputs 4. In osteoarthritis, SEMA6D overexpression protects cartilage by inhibiting the angiotensin II/IL-1β axis, enhancing extracellular matrix homeostasis 5. Clinically, SEMA6D variants associate with cognitive decline in APOE-ε4 carriers 6, Behçet's disease susceptibility 7, and brain structure in reading disability 1. Urinary SEMA6D shows promise as a non-invasive bladder cancer biomarker 8. These findings establish SEMA6D as a pleiotropic neuroimmune regulator with therapeutic potential across neurodegeneration, cancer immunotherapy, and inflammatory diseases.