The Role of Siglec-15 in Tumor Immunity: Mechanisms and Therapy

Siglec-15, a member of the sialic acid-binding immunoglobulin-like lectins (Siglec) 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-mediated T-cell immunosuppression. Notably, Siglec-15 exhibits nonredundant expression with PD-L1, suggesting its compensatory role in immune evasion mechanisms within a PD-L1-negative tumor microenvironment. 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.