huSIGLEC15 Mouse

SIGLEC15 encodes sialic acid-binding immunoglobulin-like lectin 15, a conserved type I transmembrane protein of the Siglec family. Under normal physiological conditions, SIGLEC15 is expressed at low levels in macrophage and dendritic cell subsets, osteoclast precursors, and certain myeloid cells. Under pathological conditions, it is markedly upregulated in tumor-associated macrophages (TAMs, M2-like phenotype), myeloid-derived suppressor cells, and various tumor cells including lung, ovarian, head and neck, thyroid, and bladder cancers, and is frequently expressed in a mutually exclusive manner with PD-L1 ^[1-3]. Functionally, SIGLEC15 regulates osteoclast differentiation through the DAP12-Syk pathway, mediating bone resorption and remodeling to maintain bone homeostasis; it also acts as an immunomodulatory molecule, binding sialylated ligands to influence myeloid cell function ^[4]. Loss of SIGLEC15 function impairs osteoclastogenesis and osteoclast activity, leading to an osteopetrosis-like phenotype. Conversely, excessive signaling or aberrant expression promotes pathological bone resorption and contributes to osteoporosis; in bone metastasis of breast cancer and other tumors, it accelerates bone destruction by promoting osteoclast formation and suppressing local T cell responses ^[5-6]. Within the tumor microenvironment, SIGLEC15 inhibits antigen-specific T cell responses and promotes TGF-β secretion, facilitating tumor immune evasion independently of the PD-1/PD-L1 axis. Genetic knockout or antibody blockade enhances antitumor immunity and inhibits tumor growth, making SIGLEC15 a promising immunotherapeutic target ^[3,7]. In addition, SIGLEC15 interacts with sialylated pathogens and participates in host antimicrobial immunity by modulating cytokine production or phagocytosis ^[1].

The huSIGLEC15 mouse is a humanized model generated via gene editing technology, in which the mouse Siglec15 endogenous extracellular domain was replaced with the human SIGLEC15 extracellular domain, the murine signal peptide and transmembrane-cytoplasmic region were preserved. This model is applicable to mechanistic studies of bone metabolism‑ and tumor immunity‑related diseases, including osteoporosis, osteopetrosis, various solid tumors, and tumor bone metastasis. It can also be used for the in vivo evaluation of combination immunotherapies targeting resistance or non‑response to existing immunotherapies, as well as for the screening, development, and preclinical in vivo evaluation of therapeutic agents such as SIGLEC15‑targeting antibodies and small molecule inhibitors.