Cluster of differentiation 47–Signal regulatory protein alpha immune checkpoint (CD47–SIRPα)

The CD47–Signal regulatory protein alpha (CD47–SIRPα) immune checkpoint is a critical regulator of the innate immune system, often referred to as the 'don't eat me' signal. CD47 is a ubiquitously expressed transmembrane protein that, upon binding to SIRPα on the surface of myeloid cells like macrophages and dendritic cells, triggers an inhibitory signaling cascade that prevents phagocytosis. This interaction is mediated by the recruitment of tyrosine phosphatases SHP-1 and SHP-2 to the cytoplasmic tail of SIRPα, leading to the dephosphorylation of myosin IIA and inhibition of the cytoskeleton rearrangement necessary for engulfment [1, 3, 8]. In many cancers, CD47 is overexpressed as a mechanism to evade immune surveillance by suppressing macrophage-mediated clearance. Therapeutic strategies targeting this axis include monoclonal antibodies and fusion proteins designed to block the CD47–SIRPα interaction, thereby restoring the ability of the immune system to identify and eliminate malignant cells [1, 10, 13]. While promising, targeting CD47 presents challenges such as 'on-target, off-tumor' toxicity, most notably anemia and thrombocytopenia, due to the high expression of CD47 on red blood cells and platelets [1, 4, 10]. Ongoing clinical trials are exploring various agents, including selective SIRPα blockers and CD47-targeting antibodies with modified Fc regions, to improve safety and efficacy [1, 7, 10].

Other names

CD47–SIRPα axisCD47–SIRPα signaling systemIntegrin-associated protein–Signal regulatory protein alphaIAP–SIRPαCD47–CD172aMyeloid checkpointDon't eat me signal

Blockade of the CD47–SIRPα interaction to inhibit the 'don't eat me' signal, thereby restoring macrophage-mediated phagocytosis and promoting anti-tumor immune responses through antigen presentation and ADCC/ADCP.