The human body has been fighting off unwanted invaders for as long as we have existed — be they bacteria, viruses, or even our own cancer cells. Every intruder, however, has had to find a way to evade the immune system. How? By mimicking the sugar structures that the body uses to protect its own cells. A team led by RNDr. Ondřej Vaněk, Ph.D. from the Faculty of Science, Charles University, has now described in detail how the Siglec-7 receptor is subject to these tricks and thus uncovered new ways to counter such tricks of cancer cells and pathogens alike.
Sugar ID Cards and Siglecs
Our immune system has developed sophisticated defence mechanisms against cancer and bacterial infections. But to use them, it must first distinguish which cells belong in the body and which represent a threat. For this, immune cells rely on glycan (“sugar”) structures on the surface of cells – something like an ID card that determines whether a cell passes through or will be destroyed.
These sugar “ID cards” are recognized by receptors called Siglecs, located on the surface of immune cells. Each has a specific role – some activate the immune response, others “put the brakes on” and dampen the response to prevent attacks against the body’s own cells. What all Siglecs share, however, is that they recognize sialic acid, a small nine-carbon molecule that often decorates surface proteins of our cells and serves as a key communication signal.
How Invaders Trick Immunity?
Under normal circumstances, this system helps immunity distinguish “self” from “non-self.” But evolution is resourceful – and some tumours (such as melanoma or pancreatic cancer) and pathogens (Neisseria meningitidis, group B Streptococcus, and viruses like HIV-1, Ebola, or more recently the well-known SARS-CoV-2) have learned to exploit this strategy. They disguise the surface of their cells and envelopes as if they were our own cells, mimicking their glycan structures, and thus hide from immune surveillance.
A major player in this process is the receptor Siglec-7, found on natural killer cells (NK cells). These “natural killers” can rapidly eliminate tumour or virus-infected cells. But if Siglec-7 recognises sialylated structures, it sends a “do not attack” signal to the NK cell, which can give the tumour or pathogen an advantage.
Czech Contribution to the Research
A key requirement for detailed research of these mechanisms was the work of the team led by RNDr. Ondřej Vaněk, Ph.D. at the Faculty of Science, Charles University. The scientists prepared and characterised several variants of the extracellular part of Siglec-7, described its stable dimerisation, and developed a method for producing double isotope-labelled protein (¹³C/¹⁵N) in mammalian cells. This opened the way to study Siglec-7 using nuclear magnetic resonance (NMR) in detail that had previously been inaccessible. These recombinant proteins, prepared at the Faculty of Science, then played a crucial role in further international studies examining how Siglec-7 recognizes tumour gangliosides or capsular polysaccharides of pathogenic bacteria.
GD3: The Tumour’s Fake Ticket In
Siglec-7 focuses on sugar structures of gangliosides, glycolipids abundantly present in the nervous system. Special attention has been drawn to ganglioside GD3, which is often overproduced in tumour cells. This glycolipid binds directly to Siglec-7 on NK cells, triggers an inhibitory signal, and thus protects the tumour from being killed. Thanks to a combination of modern methods – NMR, fluorescence assays, and computer modelling – scientists succeeded in describing the molecular details of Siglec-7 binding to ganglioside GD3.
The study showed that ganglioside binding to Siglec-7 is primarily mediated by the amino acid arginine 124, which forms a stable contact with sialic acid. Also important are conformational differences among gangliosides – in other words, how their sugar parts are arranged in space. These can decisively determine whether Siglec-7 recognizes a ligand and sends the inhibitory signal. This confirms the role of Siglec-7 as a glyco-immune checkpoint, which tumour cells can exploit to suppress NK cell cytotoxic response. Detailed structural knowledge of these interactions opens the door to new options in immunotherapy – from antibodies and vaccines to small molecules specifically blocking the Siglec-7–ganglioside axis.
Bacteria in Sugar Armor and the Path to New Therapies
Recent collaborative studies have built upon the work of Dr Vaněk’s team, focusing on the role of the Siglec-7 receptor in its interaction with the surface carbohydrates of pathogenic bacteria such as Neisseria meningitidis, the causative agent of meningitis, or Fusobacterium nucleatum, a bacterium quite common not only in our oral cavity, but unfortunately also in a number of cancers, e.g. colorectal cancer. These studies have likewise shown that Siglec-7 acts as a “molecular brake” on the immune response. The findings not only reveal the sophisticated strategies by which pathogens and tumours evade immune attack but also open the door to new forms of cancer immunotherapy – for example, by blocking Siglec-7 binding to help the body once again recognise the “enemy.”
Studies were published in International Journal of Biological Macromolecules (2025), Advanced Science (2025), and JACS Au (2025).
Abreu, Celeste, et al. “Insights into Stability, Dimerisation, and Ligand Binding Properties of Siglec-7: Isotope Labelling in HEK293 Cells for Protein Characterisation by NMR Spectroscopy.” International Journal of Biological Macromolecules 309, 142672 (2025). https://doi.org/10.1016/j.ijbiomac.2025.142672
Di Carluccio, Cristina, et al. “Insights into Siglec‐7 Binding to Gangliosides: NMR Protein Assignment and the Impact of Ligand Flexibility.” Advanced Science 12, e2415782 (2025). https://doi.org/10.1002/advs.202415782
Di Carluccio, Cristina, et al. “Molecular Basis of Siglec-7 Recognition by Neisseria meningitidis Serogroup Y CPS: Implications for Immune Evasion.” JACS Au 5, 2257–2269 (2025). https://doi.org/10.1021/jacsau.5c00214
Di Carluccio, Cristina, et al. “Fusobacterium nucleatum Lipopolysaccharides O-Antigen Defines a Novel Siglec-7 Binding Epitope.” JACS Au, in press. https://doi.org/10.1021/jacsau.5c00810