Siglec-15 as multifunctional molecule involved in osteoclast differentiation, cancer immunity and microbial infection.

Siglec-15 is a highly conserved member of the Siglec family, expressed on osteoclasts, a subset of myeloid cells and some cancer cells. Except for regulating osteoclast differentiation, Siglec-15 engages in immunoregulation as an immune suppressor. Siglec-15 functions as an immunosuppressive molecule in tumor-associated macrophage-mediated T cell immunity in the tumor microenvironment (TME), which makes Siglec-15 to be an emerging and promising target for normalization cancer immunotherapy. Besides, Siglec-15 interacts with sialylated pathogens and modulates host immune response against microbial pathogens by altering cytokine production and/or phagocytosis, which further broadens the underlying pathophysiological roles of Siglec-15. The fact that N-glycosylation and sialylation of Siglec-15 play a pivotal role in Siglec-15 biological function indicates that targeting certain post-translational modification may be an effective strategy for targeting Siglec-15 therapy. In-depth exploring Siglec-15 biology function is crucial for better design of Siglec-15-based therapy according to different clinical indications.