Cluster of differentiation 47-signal regulatory protein alpha interface (CD47-SIRPα)

The Cluster of differentiation 47-signal regulatory protein alpha (CD47-SIRPα) interface is a pivotal innate immune checkpoint that functions as a "don't eat me" signal to prevent the phagocytosis of healthy cells [3, 6]. 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 pathway mediated by SHP-1 and SHP-2 phosphatases [1, 4]. This interaction prevents the accumulation of myosin IIA at the phagocytic synapse, effectively blocking the engulfment of the target cell [3, 4]. Many types of cancer, including both hematological malignancies and solid tumors, exploit this mechanism by overexpressing CD47 to evade immune surveillance [5, 8]. Therapeutic agents such as monoclonal antibodies and SIRPα-Fc fusion proteins are designed to disrupt this interface, thereby unmasking "eat me" signals and promoting the clearance of malignant cells by the innate immune system [9, 10]. Beyond direct phagocytosis, blockade of this axis may also enhance adaptive immunity by facilitating the cross-presentation of tumor antigens by dendritic cells to T cells [7, 8]. However, the widespread expression of CD47 on red blood cells presents a significant safety challenge, as blockade can lead to on-target toxicities such as anemia and hemagglutination [11, 17]. Clinical development has focused on mitigating these risks through strategies like priming doses or engineering antibodies with reduced red blood cell binding [3, 13].

Other names

CD47-SIRPα axisCD47-SIRPα signaling systemMyeloid checkpointPhagocytosis checkpointCD47-SIRPα pathway

Blockade of the CD47-SIRPα interaction to inhibit the 'don't eat me' signal, thereby restoring macrophage-mediated phagocytosis and potentially bridging innate and adaptive immunity through enhanced antigen presentation.