How Sialic Acid Regulates Tumor Immunity
In March 2026, a team led by Matthew S. Macauley from the University of Alberta published a review in Journal of Biological Chemistry entitled "Writers and readers of sialylation in immunoregulation in cancer." This review systematically summarized the key role of sialylation in tumor immune regulation, focusing on how sialyltransferases, acting as "writers," and Siglec/Selectin, acting as "readers," jointly shape the tumor immune microenvironment. The article discusses in detail the mechanisms of Aberrant Sialylation in immune escape, tumor metastasis, and treatment resistance, and summarizes emerging glycan immunotherapy strategies such as Siglec-targeted therapy and sialidase conjugates.
This review systematically elucidates how sialylated glycans participate in tumor immune regulation in cancer. Tumor cells enhance surface sialylation, forming a high-density glycocalyx barrier, which not only promotes metastasis, drug resistance, and vascular adhesion, but also inhibits the function of NK cells, T cells, and macrophages through receptors such as Siglec. This article focuses on how sialyltransferases, acting as "writers," generate tumor-associated glycoantigens such as sTn, sLex, and polySia, and how Siglec and Selectin, acting as "readers," mediate immune escape and metastasis.
Overall, the Siglec–sialoglycan axis is becoming an important glycoimmune checkpoint after PD-1/PD-L1. In the future, targeting sialyltransferases, the Siglec pathway, or using antibodies to deliver sialidase for local desialylation holds promise for providing new breakthroughs in cancer immunotherapy.
Sialic Acids are nine-carbon acidic monosaccharides located at the ends of sugar chains and are an important component of the cellular glycocalyx. Due to their stable negative charge, they significantly affect intercellular interactions, receptor recognition, and the immune system's distinction between self and non-self.
Under normal circumstances, sialylation helps maintain tissue homeostasis and immune tolerance, but in cancer, this system is completely reprogrammed. Tumor cells often exhibit significant hypersialylation, forming a thick, strongly negatively charged glycan barrier on the cell surface. This structure not only reduces the recognition efficiency of immune cells but also helps tumor cells resist complement attack, inhibit NK cell killing, and promote tumor cell migration and extravasation.
The article points out that many classic tumor-associated glycoantigens (TACAs) are essentially aberrantly sialylated structures, including Sialyl-Tn (sTn), sialyl-Lewis X (sLex), sialyl-Lewis A (sLea), polySia, and gangliosides such as GD2/GD3. These structures are widely present in various tumors, including breast cancer, pancreatic cancer, gastric cancer, lung cancer, and neuroblastoma, and are typically associated with stronger metastatic potential, more severe immune escape, and poorer prognosis.
More importantly, these glycans are not merely biomarkers; they are functional molecules that are actually involved in immune regulation.
This article systematically summarizes several classic sialylated tumor biomarkers. The most well-known is CA19-9. Many people are unaware that CA19-9 is essentially a Sialyl-Lewis A (sLea) Antigen. Currently, it is widely used in the diagnosis and monitoring of pancreatic cancer and biliary tract tumors. Because sLea promotes adhesion between tumor cells and vascular endothelium, it is not only a detection indicator but also directly involved in the tumor metastasis process.
Figure 1. Sialylated TACAs reported in cancers. (Decloquement, et al. 2026)
Another important molecule is sLex. It is highly expressed in various malignant tumors such as lung cancer, breast cancer, and gastric cancer, and promotes tumor cell extravasation and distant colonization through interaction with Selectin, thus it is usually associated with high metastasis. sTn antigen is one of the most classic oncofetal antigens. It is almost not expressed in normal tissues but is significantly elevated in malignant tumors such as breast cancer, gastric cancer, and pancreatic cancer. This abnormally truncated O-glycan has long been considered an important potential target for Cancer Vaccines and CAR-T therapy.
The article also specifically mentions Neu5Gc, a unique sialic acid. Since the human body lacks the CMAH enzyme, it theoretically cannot synthesize Neu5Gc. However, many tumor cells accumulate Neu5Gc structures through metabolic uptake and other means, further enhancing their Siglec binding capacity, thus helping tumors establish a stronger immunosuppressive environment.
Abnormal sialylation in tumors is not random; the real driving force behind it is sialyltransferases (STs). The authors refer to them as the "writers" of sialylation. These enzymes are mainly located in the Golgi apparatus and are responsible for transferring sialic acid to the ends of glycans, thereby generating various different sialylated structures. Currently, 20 ST enzymes have been discovered in humans, mainly divided into four families: ST3GAL, ST6GAL, ST6GALNAC, and ST8SIA. Different families are responsible for different types of sialic acid linkage, thus collectively shaping the highly complex human sialoome.
The authors emphasize that glycan alterations in cancer are not the result of a single enzyme acting independently, but rather the synergistic effect of multiple ST enzymes. Different STs exhibit substrate overlap, functional compensation, and complex dynamic regulation, which is a key reason for the strong heterogeneity of tumor glycans.
The ST3GAL family is significantly upregulated in various cancers, including melanoma, pancreatic cancer, liver cancer, and ovarian cancer. ST3GalI is the most extensively studied among them. ST3GalI promotes the formation of sialyl-T antigens from mucins such as MUC1, which further binds to Siglec-7 and Siglec-9, thereby inhibiting NK cell activity. Simultaneously, it enhances EGFR-related signaling pathways, promotes EMT, enhances invasiveness, and improves tumor tolerance to chemotherapy drugs.
The article mentions that in ovarian cancer, high ST3GAL1 expression is closely associated with paclitaxel resistance; in glioblastoma, its high expression is associated with increased tumor invasiveness and stemness. This indicates that the ST3GAL family not only participates in immune evasion but also directly promotes tumor malignant evolution.
Among all ST enzymes, ST6GalI can be considered a core player in cancer glycobiology. The article points out that ST6GalI is significantly upregulated in various tumors, including colorectal cancer, breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer, and is closely related to metastasis, drug resistance, and poor prognosis. The most important role of ST6GalI is the α2-6 sialylation modification of various membrane receptors, including β1-integrin, PDGFRB, Fas, and TNFR1. Such modification alters receptor stability, membrane localization, and downstream signal transduction, thereby enhancing tumor cell survival.
Particularly noteworthy is that ST6GalI can inhibit Fas-mediated apoptosis. In other words, tumor cells not only evade immune killing through gene mutations but also reduce their own susceptibility to death through glycan modification.
Furthermore, ST6GalI is also involved in tumor metabolic reprogramming, hypoxia adaptation, and exosome-related regulation. The article even mentions that ST6GalI can be released into the extracellular environment in a soluble form, further enhancing the invasive ability of surrounding tumor cells.
ST6GalNAcI is a key enzyme in sTn antigen formation. It prematurely sialylates GalNAc, preventing further elongation of the glycan chain and ultimately forming the typical Truncated O-Glycan chain. Due to the high tumor specificity of sTn, ST6GalNAcI has long been considered an important therapeutic target. The article mentions that in lung adenocarcinoma, ST6GalNAcI can modify NECTIN2 and MUC5AC, thereby enhancing T cell immunosuppression, promoting angiogenesis, and driving liver metastasis.
ST6GalNAcIV contributes to Siglec-7 ligand formation in acute leukemia cell lines. In hepatocellular carcinoma (HCC), it sialylates TGFBR2, thereby enhancing TGF-β signaling, promoting tumor invasion, and reducing CD8+ T cell infiltration. These results indicate that some ST enzymes are not merely glycan processing enzymes, but rather core regulatory nodes truly involved in shaping the tumor immune microenvironment.
The ST8SIA family is primarily responsible for sialylation of the α2-8 linkage. ST8SIA2 and ST8SIA4 are the key polysialyltransferases responsible for polySia formation, whereas ST8SIA1 (also known as GD3 synthase) catalyzes the synthesis of b-series Gangliosides such as GD3 and GT3. PolySia initially gained attention primarily in neurological research, but in recent years it has been found to be highly expressed in tumors such as neuroblastoma, glioma, and lung cancer, and is closely related to tumor migration, EMT, stemness maintenance, and immune escape.
The article specifically points out that high ST8SIA4 expression is often accompanied by upregulation of inflammation-related cytokines and enhanced Siglec-10 expression, suggesting that polySia may be involved in constructing a new glycan immune checkpoint network.
If STs are responsible for "writing glycans," then Siglecs are the immune receptors responsible for "reading glycans." Siglecs are mainly expressed on the surface of NK cells, macrophages, dendritic cells, neutrophils, and some T cells. They can recognize sialylated glycans and transmit inhibitory signals to immune cells, thereby reducing immune activation levels. The authors emphasize that the Siglec–sialoglycan axis is essentially very similar to PD-1/PD-L1 and is therefore being considered as a new generation of glyco-immune checkpoints.
The article points out that tumor cells, by highly expressing sialylated glycans and binding to Siglec, can inhibit ROS production, reduce T cell proliferation and cytotoxicity, promote M2 macrophage formation, and weaken antigen presentation capabilities. This means that tumors do not rely solely on a single immune checkpoint but rather utilize an entire glycan network to systematically suppress the immune response.
Among all Siglecs, Siglec-7 and Siglec-9 are currently the two most researched members. Siglec-7 is found mainly on NK cells and certain myeloid populations such as monocytes, macrophages, and dendritic cells, whereas Siglec-9 is broadly expressed across neutrophils, monocytes, subsets of DCs, NK cells, and activated T cells. Tumor cells inhibit immune killing by expressing sialylated structures such as disialyl-T, GD3, MUC1, MUC16, and CD43.
The article mentions that molecules such as CD43, PSGL-1, and CD45 in leukemia cells can act as Siglec-7 ligands, helping tumor cells evade NK cell clearance. Siglec-9, on the other hand, is more inclined to recognize structures such as sLex and participates in T cell suppression and neutrophil function suppression in tumors such as lung cancer, breast cancer, and AML. The authors particularly emphasize that many hypersialylated tumors respond poorly to PD-1 therapy, potentially due in part to concurrent activation of the Siglec-related glycan immune checkpoint system.
Besides Siglecs, Selectins are also important sialylic glycan "readers." Selectins recognize sialylated and fucosylated structures such as sLex and sLea. Normally, this system is responsible for leukocyte homing and inflammatory migration; however, in cancer, tumor cells "steal" this mechanism.
Tumor cells that highly express sLex can roll, adhere, and eventually extravasate onto the vascular endothelial surface, just like leukocytes, thus establishing distant metastases. This is why many high-sLex tumors often have a strong metastatic potential.
Figure 2. Immunotherapy strategies based on Siglecs/Selectins interactions with their sialylated ligands in the tumor cell microenvironment of cancer. (Decloquement, et al. 2026)
The article concludes by summarizing several rapidly developing anti-sialylation treatment strategies, including Sialyltransferase Inhibitors, Siglec antibodies, Siglec CAR-T, and tumor-targeting sialidase conjugates. Among these, local desialylation is of particular interest. Because the Siglec system is essentially a normal immune tolerance mechanism, systemic suppression could lead to severe autoimmune side effects. Therefore, many studies are now attempting to remove sialic acid only from the tumor surface to restore the immune system's ability to recognize tumors.
For the past few decades, tumor immunotherapy has primarily revolved around protein receptors. This review, however, clearly demonstrates that glycans are not merely passive decorations, but rather information molecules that truly participate in immune regulation. Tumor cells establish a comprehensive network of glycan immune checkpoints parallel to the PD-1/PD-L1 system by remodeling sialylated glycocalyxes. The siglec–sialoglycan axis not only participates in immune escape but also profoundly influences tumor metastasis, metabolic reprogramming, EMT, and drug resistance formation.
With advancements in glycobiology, immunology, and antibody engineering, glycan immunotherapy is likely to evolve from a relatively niche approach into a major battleground in cancer treatment, much like PD-1 did in its early days.
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