Review of the potential effects of sialic acid and sialic acid binding receptors during embryo implantation in infertile women

Authors

Abstract

Despite advancements in assisted reproductive technologies (ART), implantation failure remains a significant challenge. Successful implantation depends heavily on maternal–fetal immune tolerance, where sialic acids and sialic acid–binding immunoglobulin-like lectins (Siglecs) emerge as crucial modulators. This systematic review explores the roles of the sialic acid–Siglec axis in embryo implantation, unexplained infertility, recurrent pregnancy loss, and recurrent implantation failure.
Evidence indicates that sialic acids are highly expressed on the trophoblast surface and endometrial glycocalyx, facilitating cell–cell interactions and immune recognition. Conversely, Siglecs act as immune checkpoint receptors that inhibit both innate and adaptive immunity. Similar to mechanisms in oncology, the sialic acid–Siglec pathway may promote immune tolerance at the maternal–fetal interface, supporting embryo adhesion and invasion. Although well-characterized in immunology and oncology, its role in reproductive medicine requires further exploration. Clarifying this pathway could provide novel biomarkers and therapeutic targets to improve ART success rates.

Keywords

Introduction

Infertility is commonly defined as the inability to conceive after 12 months of unprotected sexual intercourse, affecting an estimated 8–12% of couples globally (although estimates can differ by age, geographic region and socioeconomic status).^1,2 Socio-demographic changes, including delayed child bearing, delayed age at marriage and greater contraceptive use have resulted in an increasing requirement of treatment and diagnosis in infertility. It is described in female, male or combined/mixed forms and it is necessary to identify the true cause of infertility in order to select a suitable therapeutic approach.^1,2,3,4 In recent years, the success of ART has improved dramatically owing to ovarian stimulation and fertilization methods and embryo culture. Despite this, implantation failure, especially post-embryo transfer still represents a major challenge for clinical pregnancy.⁵
Endometrial receptivity is a highly regulated, hormone-dependent process mediated by signaling pathways that include cellular architecture, adhesion molecules and immune modulation. Despite recurrent efforts to find reliable biomarkers of receptivity, none has been yet introduced in the clinical practice at a global scale.⁶ Hence, new molecular pathways need to be studied in developing a coherent picture of the overall regulation of embryo-endometrial crosstalk.⁷
Sialic acids (SA), which are terminal monosaccharides attached to the glycan chains of glycoproteins and also on glycolipids, are enriched at cell surfaces.^8,9,10 Interactions between Siglecs, a family of sialic acid–binding immunoglobulin-like lectins predominantly expressed by cells of the immune system, and glycans bearing terminal sialic acids have been shown to modulate immune activation, tolerance, and inflammation.^8,11,12 Indeed, pathogens and tumors manipulate sialylation to evade immune surveillance.^{13,14,15,16,17} Based on this information, it is reasonable to think that analogous mechanisms could be involved in pregnancy where the semi-allogeneic embryo must avoid maternal immune attack.
The aim of this review was to summarize current evidence regarding the role of the sialic acid–Siglec axis in embryo implantation, maternal–fetal immune tolerance, and infertility, and to evaluate its potential as a diagnostic and therapeutic target in reproductive medicine.

Materials and Methods

A narrative literature review was performed using PubMed and Google Scholar. Keywords were sialic acid, Siglecs, embryo implantation, endometrial receptivity, maternal–fetal immune tolerance, recurrent implantation failure and unexplained infertility. Papers focusing on sialic acid expression, Siglec engagement/signal and immune modulation in trophoblast and endometrial cells were selected. Relevant data were extracted, summarized, discussed, and synthesized thematically.
Embryo Implantation and Immune ToleranceThe process of embryo implantation includes apposition, adhesion and invasion of the blastocyst into the receptive endometrium in a limited “window of implantation”, and in natural cycles, endometrial receptors (receivers) appear on the 16th-22nd days. This complex interplay involves precise timing of embryonic signals and endometrial structural, molecular and immunological adaptations. Implantation requires communication between the endometrium and the embryo.^18,19 With the effect of paracrine, the embryo in the tuba begins to prepare the endometrium for implantation.
In implantation, morphological modification of the endometrial epithelium, known as plasma membrane transformation, with associated microvillar retraction and pinopode development in the endometrial epithelial cells provide optimal attachment sites for blastocyst adhesion.^20,21,22 Pinopots seems to be the most trustworthy morphological marker for receptive endometrium at the time of implantation ²³ and indicate the optimal binding sites for blastocyst habitation.^22,24 Remodeling of the cytoskeleton (in particular actin filaments) and increased adhesion molecules such as integrins and CD98 are also important for trophoblast adhesion stability.^{25,26,27,28,29,30,31}
At the same time, the mother’s immune system is dynamically adjusted to allow survival of the embryo while preserving defense against pathogens. This balance is maintained hormonally,³² cytokine signaling-wise,³³ through regulatory T cells,³⁴ mucins ³⁵ and branch specific embryonic signals with direct immune modulatory functions.³⁶ The loss of immune tolerance is being increasingly recognized as a cause for implantation failure and early pregnancy wastage.
Considering all the data mentioned above, it is reasonable to ask whether sialic acids and Siglecs play a significant role in maternal-fetal immune tolerance and, consequently, whether the proper functioning of this system has positive or negative effects on embryonic implantation success.
Sialic Acid in Reproductive BiologyThe surfaces of all vertebrate cells are lined with a dense and complex series of sugar chains, which often bind to proteins and lipids.³⁷ Most dissolved and secreted proteins are similarly covered with these glycans. Sialic acids are a family of negatively charged nine-carbon monosaccharides most often found at the end of glycan chains (such as glycoprotein, glycolipid, and glycosaminoglycans).³⁸ The reason for the presence of glycan chains in terminal positions is that sialic acids are generally the most recently added sugar during the glycosylation process. The synthesis of sialylated structures also depends on the presence of the donor, which is synthesized in the nucleus by the enzyme cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) and then transported to the Golgi via the carrier.^39,40 An amino group at position C-5 characterizes these members of the carbohydrate family. Given their location and ubiquitous distribution, sialic acids can mediate a wide variety of physiological and pathological processes. Their biosynthesis and presentation are under stringent control, and is dynamically modulated in immune activation and cellular differentiation.
This diversity and plasticity in sialic acids is used by the immune system to provide regulatory mechanisms in a variety of immune cells. One of the main characteristics of the immune system is the extraordinary capacity of the organism to distinguish itself from the foreign antigen and respond accordingly. Some molecular interactions allow the stimulation of acquired immune responses when a foreign antigen is recognized, while others regulate the suppression of inflammation or the emergence of tolerance towards their own antigens. Therefore, it should not be surprising that a large number of enzymes also contribute to post-synthesis regulation of sialic acid during the development and activation of natural or acquired immune cells while controlling the presence of sialic acid on sialoglycoconjugates.
All glycans, such as SA, are detected by glycan binding receptors produced in immune cells such as C-type lectin receptors (CLRs) and Siglecs, which trigger a specific response to these sugars by inducing tolerogenic or immunogenic signaling pathways. Glycans found in healthy or malignant tissues, inflammatory cells, or pathogens provide signals to recognize “own” or “foreign” antigens.⁴¹ Glycans are part of proteins (glycoproteins), lipids (glycolipids) of host cells or pathogens and are of increasing interest by researchers as key molecules in regulating immunity and tolerance.⁴²
The main role of sialic acids in the immune system is thought to be due to the fact that they contain ligands for Selectin, C-type or calcium-dependent lectins that regulate the rolling of leukocytes as part of the targeting process. As a matter of fact, sialic acids are critical components of most ligands of the selectin family of cell adhesion molecules.^8,43 Activation of immune cells appears likely to be associated with a decrease in cell surface sialic acids mediated by a specific sialidase.^44,45
In addition, sialic acids present in the circulating follicle stimulating hormone (FSH) or luteinizing hormone (LH) (gonadotropic hormones), produced from the pituitary gland are involved in optimization of reproductive cycle by establishing half-life of these hormones.⁴⁶ There is considerable evidence to indicate that other glycans impact fertilization, not only at the sperm-egg interface and membrane fusion,⁴⁷ but also during interactions of sperm with the female reproductive tract surfaces and fluids leading to the ovum.⁴⁸ There is an agglutinin recognizing sialic acids in endometrium ⁴⁹ and it was observed that the sialic acids are involved in fertilization directly in some systems.⁵⁰ Genetic ablation of sialic acid pathways in model organisms is early embryonically lethal and are hence essential for development.^51,52
In summary, during the reproductive process, sialic acids affect gonadotropin stability, sperm-egg interaction, and embryonic development. Furthermore, sialylated glycans are abundant in the endometrium and play a role in paracrine signaling during implantation.
Siglecs and Maternal–Fetal Immune RegulationSiglecs are a family of sialylated ligands-recognizing immune-regulatory receptors in cis or trans configurations.^8,11,12,41 Some Siglecs, however, do not bind sialic acid ligands despite their nomenclature, although others can bind to sialocytes in vitro but are capable of engaging different anionic biological entities in vivo.⁵³ Siglecs have been already identified on hematopoietic system cells including here leukocytes, especially in macrophages and dendritic cells.⁵⁴ In fact, Siglecs are leukocyte-expressed ligands mediating immune recognition and adhesion events as well as pathogen uptake (including sialic acid-containing ones) by macrophages and dendritic cells.⁵³ The majority of Siglecs carry inhibitory signaling motifs such as immunoreceptor tyrosine-based inhibition motif (ITIM) in their cytoplasmic tails,^53,55 which equipped them with immune checkpoint activity to dampen excessive inflammation and maintain tolerance, but some lack these inhibitory signaling motifs.
It is important to stimulate immunity in cancers and infections when considering the treatment process, on the other hand, it is necessary to suppress the overactive immune system in allergies and autoimmune diseases. Interestingly, both pathogens and tumor cells use advanced expression of sialic acids as a mechanism that changes the immune system in their favor, indicating that the sialic acid-siglec axis is a key regulator in infection and cancer.^17,56,57 In the reproductive tract, Siglecs are expressed on both immune and epithelial cells. Similar to immune evasion by tumor and pathogen tolerance, Siglec engagement by trophoblast-sialylated ligands may suppress maternal immune effector cells in order to support embryo implantation and placental formation.^58,59,60 Also, presence of Siglecs is found to be accessory for sperm survival as well as immunomodulation.⁶¹
On this basis, it is observed that the sialic acid-Siglec axis has been partly studied—although somewhat insufficient—in terms of reproductive system and embryo implantation to date.
Ethical ApprovalNot applicable.
Statistical AnalysisNot applicable.
Reporting GuidelinesThe study was conducted in accordance with the SANRA recommendations for narrative review articles.

Limitations

The evidence regarding the role of the sialic acid–Siglec axis in embryo implantation remains limited. Most available data are derived from experimental studies, and further clinical research is needed to confirm these findings.

Conclusion

Embryo implantation is still a key factor determining the success of assisted reproductive treatments; however, poor endometrial receptivity is one of important issues that lack effective solution. Recent evidence implicates the role of sialic acid–Siglec axis in regulating maternal–fetal immune tolerance at implantation. Understanding the mechanisms involved in sialylation-dependent trophoblast–endometrial interaction and Siglec signaling between them may serve as new diagnostic markers and therapeutic targets for impaired implantation in infertile women.

Declarations

Abbreviations

ART: Assisted reproductive technologies
CMAS: Cytidine monophosphate N-acetylneuraminic acid synthetase
FSH: Follicle-stimulating hormone
ITIM: Immunoreceptor tyrosine-based inhibitory motif
LH: Luteinizing hormone
SA: Sialic acid
Siglec: Sialic acid-binding immunoglobulin-like lectin

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About This Article

Received:

March 31, 2026

Accepted:

June 7, 2026

Published Online:

June 22, 2026