The diverse functions of Siglec-15 in bone remodeling and antitumor responses

Abstract Siglec-15 is an immunoreceptor that binds to its ligand to exert diverse functions in osteoclast development, bone resorption, and even tumor-associated macrophage–mediated T cell immunity. Siglec-15 is a highly conserved member of the Siglec family and is constitutively expressed in osteoclasts, macrophages and dendritic cells. The activation domain in Siglec-15 can transmit a positive signal to regulate osteoclastogenesis via the formation of a complex with DAP12. In tumors, Siglec-15 is negatively regulated by IFN-γ, thus influencing effector T cell-mediated antitumor immunity. Importantly, this tumor-associated function of Siglec-15 is similar to that identified for PD-L1/PD-1 in normalization cancer immunotherapy. Cell-directed therapies are increasingly urgent and of clinical interest for their potential for reduced side effects and increased safety. Therefore, targeting Siglec‑15 might lead to novel discoveries for the clinical treatment of bone and tumor diseases or related diseases.