The mechanism of action of Siglec-9 in tumor immune escape

Author: Senior Product Manager of UA Views：701

The Siglec family (sialic acid binding immunoglobulin like lectins) act as glycoprotein receptors on the surface of immune cells, participating in immune regulation by recognizing sialylated glycosides. Siglec-9 is mainly expressed on the surface of immune cells such as monocytes and macrophages, and its role in tumor immunity has not been clearly defined before.

Recent Advances
Product Information

Recent Advances

I. Research Background and Scientific Questions

Tumor cells evade immune surveillance through various mechanisms, among which the remodeling of the immune microenvironment is a key link. Traditional studies suggest that tumors mainly domesticate immune cells through non-contact methods such as secreting chemokines and TGFβ. A study published in Nature Immunology in 2016 revealed a new contact-based domestication mechanism: abnormally sialylated glycans on the tumor cell surface mucin MUC1 can regulate the function of monocytes/macrophages by binding to Siglec-9 on the surface of immune cells.

The Siglec family (sialic acid-binding immunoglobulin-like lectins), as glycoprotein receptors on the surface of immune cells, participate in immune regulation by recognizing sialylated glycans. Siglec-9 is mainly expressed on the surface of immune cells such as monocytes and macrophages, and its role in tumor immunity has not been clarified before. This study focuses on the interaction between abnormal glycosylation of MUC1 and Siglec-9, providing a new perspective for understanding tumor immune evasion.

II. Specific Binding Between Abnormally Sialylated MUC1 and Siglec-9

MUC1 is a glycoprotein highly expressed in various tumors, and changes in its glycosylation pattern are closely related to tumor progression. The study constructed three MUC1 variants:

MUC1-ungly: containing only the protein backbone without glycosylation modification;

MUC1-T: with basic glycosylation but no sialylation;

MUC1-ST: with both glycosylation and sialylation (abnormal modification).

Experiments showed that only MUC1-ST could specifically bind to monocytes/macrophages, and this binding depended on sialylation modification. Further studies found that MUC1-ST mainly bound to Siglec-9 on the surface of monocytes/macrophages, and the use of anti-Siglec-9 antibodies could significantly block this interaction, confirming that Siglec-9 is the key receptor for MUC1-ST.

Figure 1: MUC1-ST binding to monocyte/macrophage Siglec-9

III. Siglec-9-Mediated Functional Changes in Monocytes

After MUC1-ST binds to Siglec-9, it significantly changes the secretion profile of monocytes:

The secretion of the pro-inflammatory factor IL-6 increases, participating in the formation of the inflammatory microenvironment;

The release of macrophage colony-stimulating factor (MCSF) increases, promoting the differentiation of monocytes into macrophages;

The angiogenesis-related factor PAI-1 is upregulated, providing conditions for tumor invasion and metastasis.

ELISA verification showed that the upregulated secretion of these factors all depended on the binding of MUC1-ST to Siglec-9, and the secretion level decreased significantly after blocking Siglec-9. In addition, MUC1-ST treatment could promote monocytes to produce nitric oxide (NO), and high concentrations of NO could inhibit T cell function, suggesting that it is involved in the construction of the immunosuppressive microenvironment.

IV. Siglec-9-Dependent Abnormal Differentiation of Macrophages

The direction of monocyte differentiation into macrophages determines the nature of the immune microenvironment. Studies found that macrophages differentiated after MUC1-ST treatment:

The expression of surface co-stimulatory molecule CD86 and IL-12 was significantly downregulated;

Significantly inhibited the proliferation of CD8⁺ T cells and the expression of the activation molecule CD69;

Also inhibited the differentiation and maturation of dendritic cells (DCs).

These effects could be reversed by Siglec-9 antibodies or IL-6 neutralizing antibodies, indicating that MUC1-ST/Siglec-9 induces the differentiation of monocytes into immunosuppressive macrophages through an IL-6-dependent manner, weakening the adaptive immune response.

V. Induction of Pro-Tumor Phenotype in Macrophages

After MUC1-ST binds to macrophages, it regulates their functional phenotype through Siglec-9:

The secretion of M-CSF, PAI-1, and epidermal growth factor (EGF) increases, participating in the regulation of macrophage self-renewal, tumor invasion, and cell proliferation;

Highly expresses M2-type macrophage markers CD206 and CD163;

The immune checkpoint molecules PD-L1 and IDO are upregulated, enhancing immunosuppression.

Functional experiments showed that the inhibitory effect of such macrophages on CD8⁺ T cells could be partially reversed by Siglec-9 antibodies, confirming the core role of Siglec-9 in the induction of the pro-tumor phenotype in macrophages.

VI. Signaling Pathway Mechanism

The traditional view is that the Siglec family transmits inhibitory signals through SHP-1, but studies found that the MUC1-ST/Siglec-9 interaction did not activate SHP-1 phosphorylation, but through a non-classical pathway:

Significantly enhanced calcium ion transport in macrophages, and this effect depended on Siglec-9;

The calcium channel inhibitor verapamil could inhibit the secretion of pro-tumor factors;

Activated the MEK-ERK pathway, and MEK inhibitors could reduce the secretion of pro-tumor factors and partially restore the proliferation ability of CD8⁺ T cells.

In conclusion, MUC1-ST activates the calcium/MEK-ERK signaling axis by binding to Siglec-9, inducing functional remodeling of monocytes/macrophages.

Figure 2: MUC1-ST activates the MEK-ERK pathway through Siglec-9

VII. Research Significance

This study reveals a new mechanism by which tumor cells domesticate monocytes/macrophages through the binding of abnormally sialylated MUC1 to Siglec-9, expanding the understanding of tumor immune evasion. This finding provides a theoretical basis for anti-tumor immunotherapy targeting Siglec-9 or abnormal glycosylation of MUC1, suggesting that antibody drugs targeting Siglec-9 or glycosylation inhibitors may become potential strategies to reverse the tumor immunosuppressive microenvironment.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

Purchase recombinant protein, choose Nanjing UA-Bio

UA protein focuses on providing various protein reagents, raw materials, and services required for drug research and development, cell therapy, gene therapy, and basic scientific research, including drug target proteins, immune checkpoint proteins, cytokines, tool enzymes, customized protein expression, and full-length transmembrane protein development. Youai is committed to providing customers with high-quality products and professional services, and building a High-tech Biological Enterprise with International Competitiveness.

Buy antibodiesFind UA www.ua-bio.com | 15 years of protein development experience

Nanjing UA Biotechnology Co., Ltd. Email：order@ua-bio.com Phone：+86-25-56221161

more products

Product Information

The Last The Next