Context-Dependent Roles of the Plexin-B Family Across Neurological, Oncological, Immune and Cardiovascular Disorders: Mechanisms and Therapeutic Implications

Plexin-B1, Plexin-B2, and Plexin-B3 are members of the Plexin-B receptor family, which engage distinct class IV semaphorins as major ligands: Plexin-B1 binds SEMA4D, Plexin-B2 interacts with SEMA4C and SEMA4B, and Plexin-B3 has been reported to bind HSPA5, while all three may participate in non-redundant ligand–receptor networks. Researchers have found receptors associated with neurological and malignant, immune-mediated, and cardiovascular diseases. However, this study strives to provide a comprehensive, cross-disciplinary synthesis of the context-specific functions of Plexin-B family members and to critically evaluate their emerging therapeutic potential across multiple disease domains. In a tumor- and context-dependent manner, Plexin-B1 and Plexin-B2 promote metastasis in glioblastoma, colorectal cancer, and triple-negative breast cancer (TNBC) through RhoA/Rac1-dependent signaling, while Plexin-B3 exhibits dual roles, acting as a tumor suppressor in TNBC under hypoxic conditions yet promoting motility in pancreatic cancer. Plexin-B regulates neuroinflammation in Alzheimer’s disease and T-cell regulation in asthma and other cardiovascular diseases via signals. This review positions the Plexin-B family as a promising yet functionally complex target for future precision medicine.