The SIRP family: from structural diversity and signaling mechanisms to implications in immune-related disease targeted therapeutics

Signal regulatory proteins (SIRPs) are membrane receptors on immune cells that control immune homeostasis and inflammation. Although SIRP family members share homologous extracellular domains, they differ in intracellular motifs and function: SIRPα transduces inhibitory signals, SIRPβ associates with DAP12 to trigger activation, and SIRPγ primarily modulates adhesion and T cell responses. This review compares the structure, ligand interactions, and signaling mechanisms of SIRPα, SIRPβ, and SIRPγ, summarizes their roles in cancer, autoimmunity and neurodegeneration, and surveys therapeutic strategies that target the CD47–SIRPα axis. We highlight current clinical progress, common toxicities, and open questions that must be addressed to advance SIRP-targeted therapies.