| SIRPα (signal regulatory protein α/SHPS1/CD172a) is an immunoglobulin superfamily transmembrane receptor highly expressed on myeloid cells, neurons, and some stromal and tumor cells, where it serves as the principal inhibitory receptor for CD47 and functions as a membrane scaffold that recruits SHP‑1 and SHP‑2 to dampen a range of activation signals, most notably phagocytosis and inflammatory effector functions. The extracellular region comprises three Ig‑like domains, with an N‑terminal IgV domain that forms the high‑affinity binding site for CD47 on opposing cells, while the cytoplasmic tail contains tandem ITIM and ITSM motifs that are phosphorylated by Src family kinases and JAK2 in response to ligand engagement or integrin and growth factor signals, creating docking sites for the SH2 domains of SHP‑1 and SHP‑2. Ligand binding by CD47 initiates SIRPα phosphorylation, SHP‑1/2 recruitment, and localized dephosphorylation of cytoskeletal and signaling substrates such as myosin IIA and components of integrin and ITAM pathways, which suppress actomyosin accumulation at the phagocytic synapse and inhibit assembly of the phagocytic machinery, thereby transmitting a potent “don’t eat me” signal that preserves healthy erythrocytes, platelets, hematopoietic stem cells, and synapses from inappropriate engulfment. In macrophages and neutrophils, SIRPα signaling also intersects with p38 MAPK and STAT3 to reduce phagocytic activity and cytotoxicity while promoting IL‑6 and IL‑17 production in specific contexts, adding a layer of cytokine modulation to its inhibitory effects on cell‑intrinsic activation programs. Tumor cells exploit this axis by upregulating CD47; engagement of SIRPα on tumor‑infiltrating macrophages and dendritic cells attenuates phagocytosis and antigen presentation, allows survival of leukemia and solid tumor cells that express strong “eat me” cues, and contributes to an immunosuppressive microenvironment. Preclinical models across hematologic and solid cancers show that genetic or pharmacologic interruption of CD47–SIRPα restores macrophage-mediated tumor cell engulfment, enhances cross‑priming and activation of tumor‑specific T cells, and reduces tumor growth, and a range of therapeutic agents—including anti‑CD47 antibodies, SIRPα‑Fc fusion decoys, and SIRPα‑blocking antibodies—have progressed into clinical development as innate immune checkpoint inhibitors. |
