Orozco-Moreno, M. | Search bioRxiv

bioRxiv2026

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

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.

cancer biology↗

bioRxiv2025

Siglec-engaging immunosuppressive sialoglycans are upregulated in prostate cancer and are targetable to suppress bone metastasis

Prostate cancer is a leading cause of male cancer-related deaths over the age of 50. New treatment options for prostate cancer are urgently needed, especially for tumours that have spread to bone. Aberrant sialylation holds substantial potential for the discovery of new therapeutic targets but has remained relatively unexplored in the context of prostate cancer, primarily due to the lack of reliable reagents for detecting tumour sialoglycans in clinical tissue. Here, we address this knowledge gap using high-affinity Siglec-based sialoglycan-binding reagents (HYDRAs) to quantify tumour sialoglycans in tissues representing the full clinical heterogeneity of prostate tumours. Using HYDRA immunohistochemistry, we show that sialoglycans that can engage Siglec-3, -7, and -9 are upregulated in primary prostate cancer tissue and sialoglycan ligands for Siglec-7 correlate with prostate cancer bone metastasis and poorer patient prognosis. Analysis of prostate-derived tumours growing in bone reveals Siglec receptors are expressed by immune cells in the bone metastatic tumour microenvironment, suggesting that this axis may play a role in immune cell functions in bone metastatic prostate cancer. Indicating this is clinically actionable, an engineered bisialidase (E-612) can effectively strip Siglec ligands from prostate cancer cells and prolong survival times of mice with bone metastasis. Our findings identify a novel mechanism involving Siglec-engaging sialoglycans in driving the growth of prostate cancer bone metastasis and demonstrate how this axis can be targeted to impede lethal prostate cancer progression.

cancer biology↗