Colorectal cancer is one of the most common cancers worldwide and is influenced by several factors, including the gut microbiota. Now, researchers have found that in colorectal cancer, the gut microbe Fusobacterium nucleatum can trigger immune cells to kill tumor cells.

The findings, published in Cell Host & Microbe, suggest that modulating the gut microbiota could be a new strategy to harness immune cells for treating colorectal cancer.

Previous studies have shown that in colorectal cancer, high levels of immune cells called neutrophils usually predict better survival, but these cells can either help tumors grow or attack them, depending on context. Fusobacterium nucleatum and other gut bacteria can both promote cancer and activate neutrophils, but it’s unclear which microbes and host factors trigger neutrophils to become tumor-killing in colorectal cancer.

So, Elisa Sorrenti at the Università della Svizzera Italiana in Bellinzona, Switzerland, and her colleagues set out to investigate how tumor-associated neutrophils in colorectal cancer are influenced by gut bacteria and genetics.

Activating immune cells

The researchers found that compared with normal tissues, tumor tissues produced higher levels of chemical signals called chemokines, which attract neutrophils.

In mice with colorectal cancer, gut bacteria—particularly Fusobacterium nucleatum—boosted the production of these chemokines, whereas other bacteria such as Bacteroides fragilis had weaker effects.

When neutrophils grown in a lab dish encountered F. nucleatum, they became activated, changed shape, moved more, and released antimicrobial proteins that might help attack tumor cells. In contrast, exposure to B. fragilis barely activated neutrophils, the researchers found.

Better survival

The tumor-killing effect depended on a receptor on the surface of neutrophils, called Siglec-14, which activates specific immune pathways. In tumors from people with colorectal cancer, a large number of tumor-associated neutrophils, together with the presence of F. nucleatum, was associated with better survival.

Overall, both the makeup of a person’s gut microbiota and the presence of the Siglec-14 receptor can determine whether neutrophils help control tumor growth, the authors say.

“Our work identifies both intratumoral microbiota composition and the host genetic makeup as critical factors for the elicitation of neutrophil cytotoxic effects and unravels Siglec-14 as a potential therapeutic target for the development of innovative immunotherapies unleashing [tumor-associated neutrophils’] cytotoxic potential,” they say.