Siglec-15 is a transmembrane protein belonging to the sialic acid-binding immunoglobulin-like lectin (Siglec) family, primarily expressed on myeloid cells (e.g., macrophages, dendritic cells) and certain tumor cells. It functions as an immune checkpoint molecule, modulating immune responses by interacting with sialylated glycans on neighboring cells. Unlike PD-L1. Siglec-15 is rarely co-expressed with PD-1/PD-L1. making it a complementary target for cancer immunotherapy, particularly in tumors resistant to existing checkpoint inhibitors.
Siglec-15 promotes immunosuppression in the tumor microenvironment by suppressing T-cell activation and enhancing the tolerogenic activity of myeloid cells. Its role in osteoclast differentiation also links it to bone remodeling, but its immunoregulatory functions have drawn significant attention in oncology.
Anti-Siglec-15 antibodies are designed to block these immunosuppressive interactions, restoring antitumor immunity. Preclinical studies show that targeting Siglec-15 inhibits tumor growth and enhances T-cell infiltration. Early-phase clinical trials (e.g., NC318 antibody) are evaluating safety and efficacy in solid tumors, with preliminary data suggesting manageable toxicity and potential therapeutic benefits.
As a novel immune checkpoint, Siglec-15 represents a promising avenue for addressing unmet needs in cancer treatment, especially for patients unresponsive to current therapies. Its unique expression profile and mechanism of action position it as a strategic target in next-generation immunotherapy development.