PLXNB1 (plexin B1) is a transmembrane receptor for semaphorin ligands, particularly SEMA4D, that regulates neuronal and vascular cell function through control of cytoskeletal dynamics and cell migration. The receptor mediates inhibitory synapse development and axon guidance by activating RhoA and modulating actin organization. Beyond its classical developmental roles, PLXNB1 has emerged as a key mediator in multiple pathological contexts. In diabetic retinopathy, SEMA4D/PLXNB1 signaling induces endothelial dysfunction and vascular leakage; blocking this pathway reduces pericyte loss and shows synergistic benefit with anti-VEGF therapy 1. PLXNB1 is implicated in neuroimmune processes: in experimental autoimmune encephalomyelitis, microglia-derived SEMA4D activates astrocytes via PLXNB1, and a CNS-penetrant EphB3 inhibitor suppresses this response 2. In Alzheimer's disease, PLXNB1 regulates peri-plaque glial net spacing and glial activation; PLXNB1 deletion reduces neuroinflammation and amyloid burden 3. Recent evidence suggests PLXNB1 deletion also reprograms tumor immunity in breast cancer, shifting macrophages toward pro-inflammatory phenotypes and enhancing anti-PD-1 efficacy 4. Pharmacological PLXNB1 blockade represents a candidate therapeutic approach for immune-mediated cancers and vascular complications of diabetes.