Siglec-15 binds mucin-domain glycoproteins with extended glycans and marks an osteoclast-like, matrix remodeling myeloid state in human tumors.

Siglec-15 has emerged as a therapeutic target in cancer, yet the glycan determinants and protein scaffolds that mediate engagement between Siglec-15-expressing myeloid cells and tumor cells remain incompletely defined. Here, we investigated the molecular basis of Siglec-15 recognition of cancer cells and examined transcriptional as well as functional programs associated with Siglec-15 expression in tumor-associated myeloid populations. Using immunoprecipitation-mass spectrometry in the pancreatic cancer cell line AsPC-1, we identified multiple mucin-domain glycoproteins enriched in Siglec-15 pulldowns. Additionally, disruption of glycan structures demonstrated that both complex N-glycans and extended mucin-type O-glycans contribute to optimal Siglec-15 binding. To define the myeloid population associated with Siglec-15 in human tumors, we interrogated publicly available single-cell RNA sequencing datasets and found that SIGLEC15 expression is enriched within a subset of tumor-associated myeloid cells exhibiting transcriptional features linked to osteoclast differentiation and extracellular matrix remodeling. Finally, in a THP-1 coculture model, Siglec-15 was further associated with DAP12-dependent tumor-induced expression of the osteoclast markers ACP5 and MMP9, together with increased release of IL-1β and IL-6. Collectively, these findings identify glycan and glycoprotein features that support Siglec-15 binding to malignant cells and associate SIGLEC15 expression with osteoclast-like and matrix remodeling myeloid programs in human cancers, providing a framework for mechanistic studies of this glyco-immune checkpoint.