Siglec-15 and its glycan ligands in tumor-associated macrophage biology and immunotherapy
- 1Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, Gelderland, Netherlands
- 2Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, Gelderland, Netherlands
Abstract
Siglec-15 has recently emerged as an important regulator at the interface of glyco-immunology and cancer-immunology. The transmembrane immune receptor links cancer-associated glycosylation to immune suppression in the tumor microenvironment (TME). Siglec-15 signals through the adapter protein DAP12, using its immunoreceptor tyrosine-based activation motif to induce signaling. While typically expressed by osteoclasts, increased expression of Siglec-15 holds critical implications for tumor-associated macrophages (TAMs). Current evidence suggests that Siglec-15 modulates anti-tumor immunity via reprogramming of TAMs toward an M2-like, protumorigenic phenotype characterized by direct suppression of effector T cells through interleukin-10 and transforming growth factor-β production. Identification of its ligands is ongoing, but Siglec-15 has been shown to interact both with N-linked and O-linked sialoglycans and binding can be enhanced by glycan sulfation. In addition, ligand specificity appears to be determined by glycan presentation on specific glycoprotein scaffolds, among others found in CD44 and CD11b. Siglec-15 expression is detected in many solid and hematological cancers and has been shown to negatively correlate with programmed cell death protein 1/programmed death-ligand 1 expression in several studies, providing rationale for targeting this Siglec. Defining the physiological and cancer-associated ligands of Siglec-15 is critical for understanding its signaling and the functional consequences thereof. Blocking antibodies for Siglec-15 show promising effects in (pre)clinical studies. Here, we provide an overview of current insights into the glycan ligands of Siglec-15, discuss its role in controlling TAMs phenotypes, and functions in the TME. Moreover, we discuss current therapeutic strategies aimed at targeting Siglec-15 and its glycan ligands in cancer immunotherapy.
Related
- GlycoRNA-related cellular program scoring identifies Siglec- and myeloid-associated tumor microenvironments for glycoRNA validation
- Combined siRNA Targeting IκBα and Stat6 Promotes Macrophage Reprogramming toward Cancer Immunotherapy
- Dual‐Targeted M1 Macrophage Extracellular Vesicles Reprogram the Tumor Microenvironment and Enhance Natural Killer Cell Immunotherapy in Breast Cancer
- Integrative bioinformatics screening of a M2 macrophage-associated gene signature for osimertinib resistance
- Deoxythymidylate Kinase (DTYMK)-Driven Pyrimidine Hypermetabolism Is Associated with a Folate-Dependent Macrophage Programme in Triple-Negative Breast Cancer
BibTeX
@article{hornikx2026siglec15,
title = {{Siglec-15 and its glycan ligands in tumor-associated macrophage biology and immunotherapy}},
author = {Daniël Hornikx and Estelle Van Lanen and Laura Palau-Grabulosa and Katharina Pape and Romana T Netea-Maier and Christian Büll and Martin Jaeger},
journal = {Journal for ImmunoTherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-015952},
url = {https://doi.org/10.1136/jitc-2026-015952},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Siglec-15 and its glycan ligands in tumor-associated macrophage biology and immunotherapy
AU - Daniël Hornikx
AU - Estelle Van Lanen
AU - Laura Palau-Grabulosa
AU - Katharina Pape
AU - Romana T Netea-Maier
AU - Christian Büll
AU - Martin Jaeger
PY - 2026
DA - 2026/10/23
JO - Journal for ImmunoTherapy of Cancer
DO - 10.1136/jitc-2026-015952
UR - https://doi.org/10.1136/jitc-2026-015952
AB - Siglec-15 has recently emerged as an important regulator at the interface of glyco-immunology and cancer-immunology. The transmembrane immune receptor links cancer-associated glycosylation to immune suppression in the tumor microenvironment (TME). Siglec-15 signals through the adapter protein DAP12, using its immunoreceptor tyrosine-based activation motif to induce signaling. While typically expressed by osteoclasts, increased expression of Siglec-15 holds critical implications for tumor-associated macrophages (TAMs). Current evidence suggests that Siglec-15 modulates anti-tumor immunity via reprogramming of TAMs toward an M2-like, protumorigenic phenotype characterized by direct suppression of effector T cells through interleukin-10 and transforming growth factor-β production. Identification of its ligands is ongoing, but Siglec-15 has been shown to interact both with N-linked and O-linked sialoglycans and binding can be enhanced by glycan sulfation. In addition, ligand specificity appears to be determined by glycan presentation on specific glycoprotein scaffolds, among others found in CD44 and CD11b. Siglec-15 expression is detected in many solid and hematological cancers and has been shown to negatively correlate with programmed cell death protein 1/programmed death-ligand 1 expression in several studies, providing rationale for targeting this Siglec. Defining the physiological and cancer-associated ligands of Siglec-15 is critical for understanding its signaling and the functional consequences thereof. Blocking antibodies for Siglec-15 show promising effects in (pre)clinical studies. Here, we provide an overview of current insights into the glycan ligands of Siglec-15, discuss its role in controlling TAMs phenotypes, and functions in the TME. Moreover, we discuss current therapeutic strategies aimed at targeting Siglec-15 and its glycan ligands in cancer immunotherapy.
SN - 2051-1426
ER -