The outermost layer of all cells is decorated with glycocalyx coatings. Sialic acid usually serves as the terminal monosaccharide of the glycocalyx. This outermost location of sialic acid makes it a critical role in mediating cellular connections between cells and the extracellular matrix. Sialic acid-containing glycans (sialoglycans) are engaged in various cellular biological processes (1) and usually combine with sialic acid-binding immunoglobulin-like lectins (Siglecs). Recent research has elucidated notable roles played by the interactions between sialoglycans and Siglecs in immune responses, thus recognizing them as crucial glyco-immune checkpoints (2, 3).

The investigation of sialoglycans in tumor immunity is now being conducted widely and rapidly. However, it is noteworthy that around the 1960s, sialic acid was concurrently recognized as a significant determinant in both tumor (4) and pregnancy (5). In these contexts, cells must evade immune surveillance—trophoblasts during gestation and tumor cells during metastatic progression—by manipulating immune checkpoint pathways. The underlying mechanisms of these two conditions are somehow similar. Tumor cells and trophoblastic epithelium are both covered with sialoglycans to escape immune attack (5, 6). This review aims to investigate the intersection of immune regulatory roles of sialoglycans in pregnancy and tumors, pointing out their potential as therapeutic targets. In order to enhance comprehension of the functions of sialoglycans in pregnancy, we investigated their roles throughout the entirety of the gestational period, as well as their overlap relevance in tumor immunity.

Sialic acids comprise a collection of more than 50 sugars with nine carbon atoms, which are derived from neuraminic acid or deaminoneuraminic acid (Kdn, Figure 1A ). The most prevalent types of sialic acids are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), and the former one is the predominant form in humans ( Figures 1B, C ) (7). Neu5Ac is subsequently carried into the nucleus and forms its activated form, cytidine 5’-monophosphate-sialic acid (CMP-Neu5Ac, Figure 1D ), by the enzyme CMP-Neu5Ac synthase (CMAS) (8, 9). The Neu5Ac moiety of CMP-Neu5Ac is transferred to the termini of glycoproteins and glycolipids by sialyltransferases (9, 10). The process of attaching sialic acids to the terminals of glycocalyx is referred to as sialylation. Enzymes known as β-galactoside α-2,3-sialyltransferases (ST3Gals), β-galactoside α-2,6-sialyltransferases (ST6Gals), and α-N-acetylgalactosaminide α-2,6-sialyltransferases (ST6GalNAcs) catalyze the attachment of sialic acids to galactose (Gal) or N-acetylgalactosamine (GalNAc) through an α-2,3/6-linkage ( Figures 1E, F ). Alpha-2,8-sialyltransferases (ST8Sias) catalyze the synthesis of polysialic acids ( Figure 1G ). Sialoglycans are divided into three classes based on the types of above glycosidic bonds: α2,3-sialoglycans, α2,6-sialoglycans, and α2,8-sialoglycans ( Figures 1E–G ). The enzymatic process of sialylation altered the glycocalyx of cells, affecting cell-cell interactions essential for immune tolerance during pregnancy and tumor immune evasion.

Maintaining the maternal-fetal immunity balance is crucial for a successful pregnancy (11). Endogenous sialoglycans, which hinder leukocyte activation via “self-associated molecular patterns” (SAMP) (12) are pivotal for the protection of the semi-allogeneic embryos. The deficiency of sialoglycans due to the genetic removal of CMAS lead to the death of embryos at around 9.5 days after fertilization in mice (13). As shown in Figure 2A , amniotic fluid concentrations of α2,3-sialoglycans and α2,6-sialoglycans are positively related to gestational weeks, suggesting their critical role in maintaining fetal tolerance (14). When complicated with preeclampsia, the concentration of total sialic acids in the saliva of pregnant women exhibited a considerable rise (15); α2,3-sialoglycans concentrations decreased in the syncytiotrophoblast and fetal endothelium of the placental terminal villi (16); levels of α2,6-sialoglycans in the syncytium elevated (17); but the serum levels of sialic acid were not significant changed (18) ( Figure 2B ). A key pathogenic factor in the development of preeclampsia is the impairment of maternal immune tolerance towards the semiallogeneic fetus (19). It is remains to be revealed if alterations in sialic acid levels in preeclampsia contribute to this immunological imbalance. Moreover, sialoglycans may commence to act even before conception ( Figure 2C ). The follicular fluid of women who successfully achieved pregnancy through in vitro fertilization may contain higher levels of total sialic acids than those who were unsuccessful (p=0.064; significance was not achieved) (20). Furthermore, sialoglycans are necessary for sperm and embryos to survive in the female reproductive tract (FRT) until delivery (21–24).

Tumor progression is partly similar to embryo implantation. The infiltration and invasion of trophoblasts during pregnancy are governed by regulation, whereas that of tumors is characterized by an unrestricted process (67). It is unknown whether these similarities and distinctions between these two conditions contribute to the solution of their complicated issues. Understanding the mechanisms that restrict the invasion of trophoblasts has the potential for developing strategies to halt the pathological proliferation of tumor cells. Similarly, conditions like inadequate remodeling of uterine spiral arteries and recurring implantation failure may be solvable by understanding the mechanisms of tumor progression.

Sialylation, a protein post-translational modification, has been researched in both pregnancy and tumors for decades. As previously discussed, sialoglycans paly crucial roles in maternal-fetal immune regulation throughout pregnancy, contributing to the survival of gametes in FRT and implantation of blastocysts ( Figure 4A ). Sialic acid is also reported to alter the conformation and flexibility of glycan chains, thus changing the protein functions (68). The presence of sialoglycans on the epidermal growth factor receptor promotes the process of epithelial to mesenchymal (ETM) transition in cancer cells (69) ( Figure 4B ). Elevated levels of sialoglycans on tumor necrosis factor receptor 1 (TNFR1) and Fas hinder apoptosis signals, allowing cancer cells to escape apoptosis as they move through the blood and lymphatic system, leading to the formation of secondary tumors (70) ( Figure 4C ). These mechanisms are also being studied in the context of pregnancy (71, 72). Therefore, it is essential to explore the overlap field of sialoglycans in tumor immunity and maternal-fetal immunity ( Figure 4 ). Recent studies have demonstrated that sialoglycan inhibitors, such as anti-Siglec antibodies, are in development for cancer immunotherapy (73, 74). These inhibitors could potentially be repurposed for addressing pregnancy-related immune disorders like preeclampsia.

The presence of Siglec-6 on trophoblast cells and Siglec-5/14 on amniotic epithelium suggests that their interaction with sialylated ligands may play a role in pregnancy (75). Siglec-6, which is uniquely expressed on human placental trophoblast, regulates cell proliferation, invasion, and apoptosis during pregnancy, and its expression in normal placentas drops markedly after eight weeks gestation (76). The dynamic expression of Siglec-6 may indicate that its downregulation serves as a brake on trophoblast invasion. Interestingly, Siglec-6 is also implicated in the progression of certain cancers, such as bladder cancer, where its expression correlates with poor prognosis (77–79). This suggests that Siglec-6 could serve as a shared therapeutic target in both contexts and implies the possibility that physiologic pregnancies hold the secret to preventing cancer invasion.

Within the amniotic epithelium, there is a pair of Siglec receptors, Siglec-5 and Siglec-14. Siglec-5 serves as an inhibiting receptor. Siglec-14 functions as an activating receptor. These receptors are essential for controlling the immune response to invasive infections caused by Group B Streptococci (80). The Siglec-5 molecule also serves as an inhibitory immunological checkpoint in specific tumor cells, and blocking it shows potential in enhancing the T cell immune response against tumors (81). Siglec-14, which shares sequence similarity with Siglec-5, increases the lipopolysaccharide-induced production of TNFα and exhibits distinct immunological properties (82). In the human genome, SIGLEC14 is located near SIGLEC5 and they share a remarkably identical sequence in the coding region at the 5’-end. The fusion gene formed by SIGLEC5 and SIGLEC14 controls the levels of Siglec-5 and Siglec-14 (82). Due to these gene signatures, the extracellular domains of Siglec-5 and Siglec-14 are structurally similar and are capable of recognizing the same ligands. However, these two Siglecs transmit signals through the activation of ITIM and immunoreceptor tyrosine-based activation motif (ITAM), respectively. Co-culture with tamoxifen-treated breast cancer cells induces an immune response of monocytes caused by the overexpression of Siglec-14 rather than Siglec-5. One potential explanation for these changes could be that tamoxifen-induced estrogen-dependent sialoglycan alterations in breast cancer cells (83). These findings imply that tamoxifen has the ability to regulate the immune system and triggers an immunotherapy response through the interaction of sialoglycans and Siglecs. The similar functions of the paired Siglec-5/14 glyco-immune checkpoint in pregnancy and malignancies suggest that the underlying mechanisms of these two conditions are interconnected and complementary.

Likewise, it has been discovered that Siglec-10 interacts with sialoglycans on CD24 in the first-trimester placenta, indicating their involvement in maternal-fetal immune tolerance (84). Siglec-10 possesses two ITIM motifs, which transmit inhibitory intracellular signals (85). The immunosuppression mediated by the interaction of Siglec-10 and CD24, which is known as an innate immune checkpoint, is also observed in tumors. Increased expression of Siglec-10 in kidney renal clear cell carcinoma is associated with a negative outcome. Its expression is potentially orchestrated by transcription factors c-FOS and GATA1 (86). GATA1 expression reaches its highest level during the process of trophoblast attachment to the maternal endometrium. This indicates that GATA1 is involved in the attachment and implantation of the conceptus (87). The investigation of GATA1’s role in regulating Siglec-10 expression during pregnancy has not yet been conducted. Thus, understanding the regulation of Siglecs expression in tumors could offer valuable insights into their expression patterns in pregnancy.

The immunological regulating of the maternal-fetal interface serves as a natural example of active immunotolerance, as it maintains a delicate balance between accepting the semiallogeneic fetus and defending against attacks from “non-self” antigens simultaneously (88). The discussion focused on the roles of sialoglycans in pregnancy and tumors as glyco-immune checkpoints. Although tumors during pregnancy are rare (approximately 1 in 1000 pregnancies), there have been reported cases of using immune checkpoint inhibitors (ICIs) (89, 90). ICIs, including monoclonal antibodies that target cytotoxic T-lymphocyte–associated protein 4 (CTLA4), lymphocyte activation gene 3 (LAG3), programmed cell death 1 (PD-1), and its ligand (PD-L1), are commonly used to treat multiple types of tumors (90). ICIs are designed to reestablish the immune response mediated by T cells against cancer cells. Nivolumab and pembrolizumab (anti-PD-1 drugs) are classified as pregnancy category D (positive evidence of risk) by the Food and Drug Administration (FDA), whereas ipilimumab (anti-CTLA-4 antibody) is labeled as pregnancy category C (risk cannot be ruled out). Preclinical studies and some reports show that administration of ICIs for treating tumors during peri-pregnancy period may raise the chances of pregnancy issues, premature birth, low birth weight, and even fetal death (89, 91). Nevertheless, there have been documented clinical instances showing positive outcomes related to pregnancy. Monotherapy with anti-PD-L1 or anti-CTLA4 did not lead to an increase in maternofetal adverse outcomes when compared to other anti-tumor medications. However, the concurrent administration of anti-PD-1 and anti-CTLA4 did lead to (90). Thus, monotherapy and close monitoring of both mothers and fetuses are necessary when administered. The immune-related adverse events here may result from the impaired immune tolerance caused by ICIs.

The establishment of immunological tolerance between the mother and fetus is crucial for the success of pregnancy. Immune system disorders are a typical reason for pregnancy loss. The immune checkpoints have been investigated to be potential biomarkers for recurrent pregnancy loss (92–94). As toxicities of ICIs on fertility, pregnancy, and sexuality have been revealed (95), their potentially therapeutic roles in recurrent spontaneous abortion were not investigated. Recently, agents targeting glyco-immune checkpoints have been studied (96, 97). GLIMMER-01’s phase I findings showed that E-602, a fusion protein made up of modified human sialidase and human IgG1 Fc region, effectively targeted immunosuppressive sialoglycans at the well-tolerated doses (97). Further assessment will be conducted on the monotherapy effectiveness of E-602 in individuals with non-small cell lung cancer and melanoma who are resistant to ICIs. Furthermore, receptors for sialoglycans, including Siglec-6 (77, 98), Siglec-10 (99, 100), and Siglec-15 (101–103), have been identified as targets for tumor therapy in clinical trials. Lirentelimab, an antibody targeting Siglec-8, has been investigated in autoimmune diseases such as chronic urticarial (104). No reports exist on the utilization of ICIs or glyco-immune checkpoint treatment for recurrent pregnancy loss. Further research is necessary to fully elucidate the role of sialoglycans in reproductive immunology. Large-scale clinical trials are required to investigate the safety and efficacy of targeting glyco-immune checkpoints in pregnancy-related complications, and parallel studies in cancer biology could provide valuable insights.

Sialoglycans are involved in the entire pregnancy period and partially overlap in tumor immunity. Restoring balance to the sialylation process may potentially resolve pregnancy-related disorders like miscarriage and preeclampsia. Given the wide-ranging studies on ICIs, agents that target glyco-immune checkpoints might be a promising therapy for both tumor and pregnancy-related diseases. Interfering with glyco-immune checkpoints to locally regulate immune responses in FRT may serve as a novel therapy with low toxicity. However, further research is required to better comprehend the roles of sialoglycans throughout pregnancy to catch up with the level of knowledge we possess about malignancies. Targeting glyco-immune checkpoints in pregnancy must be approached with caution, as there is a delicate balance between immune tolerance and protection. Disruption of this balance could potentially result in adverse outcomes, such as increased susceptibility to infections or pregnancy complications.