CD47

Class

Monoclonal antibody (anti-CD47 innate immune checkpoint blocker, IgG4)

Pathway

CD47-SIRPα 'don't eat me' signal blockade, restoring macrophage-mediated phagocytosis

CD47 is a cell-surface protein expressed broadly across normal and malignant cells that functions as a signal to phagocytic immune cells, chiefly macrophages, marking a cell as one that should not be engulfed. It does this by binding SIRPα, an inhibitory receptor on macrophages, delivering a 'don't eat me' signal that restrains phagocytosis. Many cancers exploit this pathway, upregulating CD47 to evade innate immune clearance even when they are otherwise recognizable as abnormal. Blocking the CD47-SIRPα interaction, whether with monoclonal antibodies against CD47 or with engineered SIRPα-Fc fusion proteins that act as decoy receptors, removes this inhibitory brake and allows macrophages to engulf and destroy tumor cells, particularly when other pro-phagocytic 'eat me' signals such as calreticulin are also present on the cell surface. This mechanism is distinct from T-cell checkpoint blockade because it operates on the innate immune system, making it of interest across hematologic malignancies and solid tumors, and potentially complementary to antibody therapies that depend on macrophage-mediated killing. Because CD47 is expressed on healthy cells, particularly red blood cells and platelets, modulating this pathway carries mechanism-based considerations that shape how such agents are designed and dosed.