Microscopy images of F. nucleatum ATCC 10953 association with immune cells. F. nucleatum ATCC 10953 is shown in red and nucleus of immune cells in blue

Researchers from the Quadram Institute collaborating with international partners have shown how complex sugar molecules produced by certain bacteria can interrupt an interaction between cancer cells and the immune system. Developing this into a therapy could block the way cancer cells evade destruction by the immune cells.

Our immune system is adept at finding invading microbes or other foreign substances that could cause disease, whilst for the most part leaving our own bodies’ cells untouched.

It also detects cancerous cells. Some cancers evade detection by mimicking the signals our own cells produce that mark themselves as safe to the immune system. In colon cancer, these signals can be in the form of sugar-based glycan molecules called sialic acids that decorate the cell surface and which expression is increased in cancer cells. Their complex structure specifically interacts with receptor molecules called Siglecs on immune cells, which inhibit the immune response.

As a result, the so-called Siglec–sialoglycan axis in colon cancer has been targeted as the basis for several therapeutic paths, so novel ways of disrupting this binding could help make these more effective.

Previously, Dr Dimitra Lamprinaki, working in Professor Nathalie Juge’s group at the Quadram Institute Bioscience showed that one of these immune cell receptors, called Siglec-7 interacts with Fusobacterium nucleatum via  microbial sugar molecules known as  lipopolysaccharides (LPS).

These bacteria are associated with colon cancer. They are enriched in the microbiome of colon cancer patients, where they are associated with poor prognosis, promoting tumour development and resistance to treatment.

In this new study, published in the journal JACS Au, the research team wanted to test whether  they could make use of these findings to disrupt the interaction between immune cell Siglec-7 and the sialic acid molecules found on cancer cells.

To answer this question, Dr Manasik Ali worked with colleagues from Raboud University in The Netherlands. Dr Ali was studying on a Marie Sklodowska‐Curie PhD studentship with Prof. Juge, as part of the European Union’s Horizon 2020 Glytunes International Training Network.

To determine whether the Fusobacterium nucleatum derived LPS molecules could interrupt the interaction of Siglec-7 with sialic acid, Manasik, as part of the training network, worked with experts at Raboud University to glycoengineer mammalian cells in order to decorate them with sialic acid molecules using ‘click chemistry’ techniques.

The glycoengineered cells showed strong interactions with Siglec-7 molecules.

This binding was significantly disrupted in the presence of LPS derived from Fusobacterium nucleatum.

Demonstrating that F. nucleatum LPS can act as potent inhibitors of the Siglec-7–sialoglycan axis is significant, as it will form the basis for targeted development of molecules that mimic how LPS block the interaction.

Developing these ‘glycomimetics’ will be aided by further insights into the chemical structure of the glycan parts in LPS that interact with Siglec-7.

The hope is that these could then be deployed to block or inhibit the Siglec–sialic acid axis colon cancer cells use to turn down an immune response.

This research received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 956758 and the Biotechnology and Biological Sciences Research Council, part of UKRI.

Reference: Fusobacterium nucleatum Lipopolysaccharides Disrupt the Interaction of Siglec-7 to Sialoglycans Expressed on Mammalian Cells, Manasik Ali, Venetia Psomiadou, Marta Tiemblo Martín, Dimitra Lamprinaki, Ferran Nieto-Fabregat, Klaudia Sobczak, Matthew S. Macauley, June Ereño-Orbea, Cristina De Castro, Alba Silipo, Thomas J. Boltje, Nathalie Juge. JACS Au 2026, 6, 3, 1643–1653 DOI: 10.1021/jacsau.5c01502