SIGLEC9 is a sialic acid-binding immunoglobulin-like lectin that functions as an immune checkpoint molecule on myeloid cells, particularly macrophages and monocytes. The protein preferentially binds alpha-2,3- or alpha-2,6-linked sialic acids on cell surfaces 1, with its recognition site potentially masked by cis interactions with sialic acids on the same cell [UniProt annotation]. Functionally, SIGLEC9 acts as an inhibitory receptor that suppresses immune cell activation and phagocytosis. On macrophages in glioblastoma, SIGLEC9 restricts T-cell priming and promotes immune evasion 2, while on NK cells, it negatively regulates cytotoxic function against hepatocellular carcinoma and other tumors 3. Tumor cells exploit this mechanism by expressing high levels of sialylated glycoproteins (including CD59) that engage SIGLEC9, driving macrophage differentiation toward immunosuppressive phenotypes with increased PD-L1 and IL-10 expression 41. In disease contexts, elevated SIGLEC9 expression correlates with poor prognosis in glioblastoma and hepatocellular carcinoma patients 53. Additionally, plasma SIGLEC9 levels show genetic association with Alzheimer's disease pathology 67. Blocking SIGLEC9-ligand interactions or deleting SIGLEC9 synergizes with anti-PD-1/PD-L1 checkpoint inhibitors to enhance antitumor immunity 25, positioning SIGLEC9 as a promising therapeutic target.