SIGLEC15 (sialic acid binding Ig-like lectin 15) functions as a critical immune checkpoint molecule that suppresses T cell responses and promotes immune evasion in cancer. The protein binds sialylated glycoproteins and is expressed on myeloid cells, including tumor-associated macrophages and osteoclasts 1. SIGLEC15 operates through distinct mechanisms: it suppresses antigen-specific T cell responses by reducing CD8+ T cell infiltration and cytotoxicity, while promoting a non-inflammatory tumor microenvironment 12. The protein inhibits T cell activation by reducing NFAT1, NFAT2, and NF-κB signaling pathways, leading to decreased IFN-γ and IL-2 secretion 3. In bone biology, SIGLEC15 regulates osteoclast differentiation and bone resorption, with anti-SIGLEC15 antibodies inhibiting osteoclast formation while stimulating osteoblast proliferation 4. Clinically, SIGLEC15 expression is mutually exclusive with PD-L1 and correlates with immunotherapy resistance across multiple cancer types 15. The protein represents a promising therapeutic target, with antibody blockade enhancing anti-tumor immunity and overcoming immunotherapy resistance in preclinical models 63. SIGLEC15 can be upregulated through metabolic pathways, including the kynurenine/AhR axis in head and neck cancers 7.