The role of Siglec-15 in tumor immunity: mechanism and therapy

Abstract Siglec-15, a member of the sialic acid-binding immunoglobulin-like lectins (Siglecs) family, has emerged as a pivotal immunosuppressive mediator and a promising therapeutic target in cancer immunotherapy. This transmembrane glycoprotein orchestrates multifaceted biological processes, such as osteoclastogenesis regulation, bone remodeling, and tumor-associated macrophage (TAM)-mediated T cell immunosuppression. Notably, Siglec-15 exhibits non-redundant expression with programmed death-ligand 1 (PD-L1), suggesting its compensatory role in immune evasion mechanisms within PD-L1-negative tumor microenvironment (TME). This review delineates the molecular architecture of Siglec-15 and elucidates its pleiotropic regulatory mechanisms. Particular emphasis is placed on deciphering its immunomodulatory functions within tumor ecosystems, while critically evaluating emerging therapeutic modalities targeting Siglec-15, spanning from preclinical validation to ongoing clinical trials.