CD47–Signal regulatory protein alpha (SIRPα) immune checkpoint interface (CD47–SIRPα)

The CD47–Signal regulatory protein alpha (SIRPα) immune checkpoint interface is a critical regulatory pathway of the innate immune system, often referred to as the 'don't eat me' signal. CD47 is a transmembrane protein expressed on nearly all normal cells, serving as a marker of 'self' by binding to SIRPα, an inhibitory receptor located on myeloid cells like macrophages and dendritic cells [PMID: 32103354]. This interaction leads to the phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on SIRPα, which recruits phosphatases to inhibit the pro-phagocytic activity of the macrophage [PMID: 28912440]. In oncology, many tumors overexpress CD47 to evade phagocytic clearance, making this interface a high-priority therapeutic target [PMID: 31110281]. Drugs targeting this axis, such as magrolimab and evorpacept, work by blocking the CD47-SIRPα interaction, thereby enabling macrophages to engulf and destroy cancer cells, often in synergy with other opsonizing antibodies [PMID: 34161771]. A significant challenge in targeting CD47 is its broad expression on healthy tissues, particularly red blood cells, which can lead to treatment-induced anemia and a large 'antigen sink' that complicates dosing [PMID: 33067318].

Other names

CD47-SIRPα axisDon't eat me signalIntegrin-associated protein-SIRPα interactionIAP-SIRPα interfaceCD47-SIRPalpha checkpoint

Blockade of the inhibitory CD47-SIRPα interaction to disrupt the 'don't eat me' signal, thereby promoting macrophage-mediated phagocytosis of target cells.