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bioRxiv · 10.64898/2026.08.07.743480

Siglec-15 is a glyco-immune checkpoint in prostate cancer regulating immune evasion and metastasis

Matthews, N.·Zeng, F.·Hodgson, K.·Fisher, M.·Peng, Z.·Blencoe, L.·Orozco-Moreno, M.·Dennis, E. P.·Lu, L.·Lawson, M. A.·Mei, S.·Sykes, D. B.·Flies, D.·Beatson, R.·Wang, N.·Munkley, J.
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Abstract

Prostate cancer is a leading cause of cancer-related mortality in men, and effective treatment options are limited for advanced and metastatic disease. The sialoglycan immune checkpoint Siglec-15 has emerged as a key mediator of tumour-associated immune suppression in several malignancies; however, its expression and functional role in prostate cancer remain poorly defined. Here, using dual immunofluorescence and immunohistochemistry, we demonstrate that Siglec-15 is expressed by prostate tumour epithelial cells, immunosuppressive macrophage phenotypes, and bone-resorbing osteoclasts within the tumour microenvironment. Mechanistically, we show that direct Siglec-15 receptor crosslinking, either by antibodies or tumour cell-derived conditioned medium, promotes monocyte-to-macrophage differentiation, generating macrophages with immunosuppressive and pathogenic phenotypes. Using therapeutic antibodies, we show that Siglec-15 blockade suppresses supernatant-induced monocyte to macrophage differentiation, allowing for the recovery of CD8 T-cell activation. Furthermore, we reveal that macrophage colony-stimulating factor (M-CSF) driven monocyte-derived macrophage differentiation is partially dependent on Siglec-15 signalling, with Siglec-15 blockade enhancing CD8 T-cell responses. In addition, anti-Siglec-15 treatment suppressed osteoclast differentiation, highlighting a dual role for Siglec-15 in prostate cancer immune suppression and bone remodelling. Consistent with these in vitro findings, therapeutic Siglec-15 blockade significantly reduced subcutaneous tumour growth in a CD8 T-cell-dependent manner and prolonged survival in a mouse model of prostate cancer metastasis. Together, these findings identify Siglec-15 as a central regulator of the prostate cancer glyco-immune axis, linking tumour-associated macrophage immune suppression with osteoclast-mediated bone remodelling, providing a compelling rationale for the clinical development of Siglec-15-targeted therapies for patients with advanced disease.

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Matthews, N., Zeng, F., Hodgson, K., Fisher, M., Peng, Z., Blencoe, L., Orozco-Moreno, M., Dennis, E. P., Lu, L., Lawson, M. A., Mei, S., Sykes, D. B., Flies, D., Beatson, R., Wang, N., Munkley, J.. 2026-08-10. Siglec-15 is a glyco-immune checkpoint in prostate cancer regulating immune evasion and metastasis. https://doi.org/10.64898/2026.08.07.743480

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