Semaphorins: from CD8⁺ T cells to cancer immunotherapy

Semaphorins were initially identified as axon guidance molecules in the nervous system, where they transmit repulsive signals to restrict axonal growth by regulating the dynamics of growth cone cytoskeletal structures. Subsequent studies have demonstrated that semaphorin signaling can restrict the migration of CD8⁺ T cell precursors driven by chemokines, thereby maintaining the corticomedullary structure of the thymus. In recent years, increasing evidence has revealed that semaphorins and their receptors (such as plexins and neuropilins) play critical roles in the lymph node homing and activation of CD8⁺ T cells, as well as in their migration and effector functions within the tumor microenvironment. This review summarizes recent advances in understanding the roles of semaphorins and their receptors in CD8⁺ T cell development, migration, and function, highlighting their potential as targets for cancer immunotherapy.