Siglec-15 is a critical immune suppressor with broad upregulation on various cancer types and a potential target for cancer immunotherapy. Siglec-15 has unique molecular features compared with many other known checkpoint inhibitory ligands. It shows prominent expression on macrophages and cancer cells and a mutually exclusive expression with PD-L1. As a new player in the cancer immunotherapeutic arena, Siglec-15 may represent a novel class of immune inhibitors with tumor-associated expression and divergent mechanisms of action to PD-L1, with potential implications in anti-PD-1/PD-L1-resistant patients. Siglecs are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. Siglec-15 consisting of immunoglobulin (Ig)-like domains, transmembrane domain and a short cytoplasmic tail. Siglec-15 is that recognizes sialylated glycans and regulates osteoclast differentiation. Siglec-15 is a potential therapeutic target for osteoporosis and plays a conserved regulatory role in the immune system of vertebrates.