SIRPA is a cell surface immunoglobulin-like receptor that functions as a critical immune checkpoint regulator with context-dependent roles in inflammation and cancer immunity. Primary function: SIRPA binds CD47 on target cells, delivering a "don't eat me" signal that inhibits phagocytosis by myeloid cells including macrophages and NK cells 12. Mechanism: CD47 ligation repositions SIRPA at the phagocytic synapse, where it recruits phosphatases (PTPN6, PTPN11) and inhibits integrin activation to suppress macrophage engulfment and NK cell killing 32. Beyond phagocytosis, SIRPA acts as a docking protein regulating dendritic cell maturation and cytokine production. Disease relevance: CD47-SIRPA overexpression enables cancer immune evasion, making this axis a therapeutic target in oncology 4. However, SIRPA exhibits cell-type-specific antagonistic effects—tumor-intrinsic SIRPA enhances anti-PD-1 immunotherapy responses in melanoma, contrasting with its inhibitory role in immune cells 5. Macrophage ID3 expression can shift the inhibitory/activating receptor balance by buffering SIRPA transcription to promote anti-tumor phagocytosis 6. Clinical significance: Blocking the CD47-SIRPA checkpoint with antibodies or small molecules shows promise in cancer immunotherapy, though challenges including anemia limit broad application 74.