The Role of Gut Bacteria in Boosting Cancer Treatment

In recent years, cancer immunotherapy has been one of the greatest advances in the field of oncology. Unlike chemotherapy and radiotherapy, this treatment does not directly attack tumor cells. Instead, it blocks checkpoints, which are molecular control points on T-cells. Tumors exploit these checkpoints to disguise themselves as harmless. When these checkpoints are blocked by medications, T-cells can again recognize and attack cancer cells.

However, this principle only works for some patients. Depending on the type of tumor, only about 50 percent respond to immune checkpoint therapy in the long term, while the treatment proves ineffective for the rest. One of the key focus areas of current cancer research is why the immune system does not respond in these cases.

This is where the Zurich Microbiome Project comes in. An interdisciplinary team at the University Hospital Zurich and the University of Zurich is investigating whether the gut microbiome — the totality of bacteria in the gut — plays a role. This idea arose from recent observations suggesting that gut bacteria affect the immune system more than previously thought. Could they therefore impact whether immunotherapy is effective?

To test this theory, patients whose tumors did not respond to immune checkpoint blockade therapy underwent fecal microbiota transplantation (FMT). The FMT was transferred via colonoscopy from donors who had responded well to the therapy. The cancer therapy itself remained unchanged.

The result is remarkable: in approximately half of the individuals who had previously been resistant to treatment, an effect on cancer therapy was observed. The immunotherapy, which had previously been ineffective, suddenly started to work.

“The transfer evidently altered the immunological and metabolic conditions in such a way that the existing therapy could take effect,” says Michael Scharl, professor of translational microbiome research at UZH and chief of service in the Department of Gastroenterology and Hepatology at USZ. From 2022 to the end of 2025, the microbiome project received CHF 1.65 million in funding from the Comprehensive Cancer Center Zurich (CCCZ). The project included contributions from a host of experts, including Anne Müller, professor of experimental medicine, and Mitchell Levesque, professor of experimental immunodermatology.

However, the study’s key finding does not only lie in the clinical observation, but in the resulting shift in perspective. In the beginning, the researchers concentrated on so-called super donors, i.e., donors with particularly favorable bacterial compositions, hoping to be able to identify certain types of bacteria that could reliably boost response rates. However, the new data tells an altogether different story: the crucial factor is seemingly not so much which bacteria are transferred but rather the immune system into which they are transplanted.

Cancer patients with a certain population of monocytes in the gut and a high diversity of T cell receptors are far more likely to benefit. These receptors determine which antigen structures a T-cell can recognize. “The broader this repertoire, the greater the chance that activated immune cells will actually identify tumor antigens,” says Scharl. Therefore, FMT does not create new immunological capabilities; it mobilizes existing ones.

How exactly this works in practice can be understood on two levels.

• Firstly, the transfer appears to alter the metabolism. The patient’s blood contains increased levels of certain unsaturated fatty acids, which can increase the oxidative stress in tumor cells. This puts tumor cells under pressure and leaves them more vulnerable to attack by the immune system.
• Secondly, FMT introduces not only individual bacteria, but rather a whole spectrum of microorganisms and their antigens into the gut. This works like a broad-based training program, whereby cytotoxic T-cells are more intensively activated and put into a state of heightened alertness. As a result, tumor cells that previously evaded detection are more likely to be detected.

It has not been possible to identify any “miracle bacteria” – the effect does not appear to be limited to a single species, but rather arises from the complex interaction between the microbiome, metabolism and individual immune system architecture.

For the research, this means shifting the focus. Instead of looking for the ideal bacterial composition, the spotlight is now on the use of precision medicine to determine the recipient’s characteristics. Which molecular and immunological markers can predict a response? Who has a sufficiently broad T-cell repertoire?

Clinically, the next step has already been set in motion. Another study is currently underway in collaboration with ZüriPharm AG to lay the groundwork for incorporating FMT into routine clinical practice in the future.

The Zurich findings therefore not only change our understanding of the gut microbiome, they also suggest that the effectiveness of immunotherapy depends on the immunological environment in which it is used. This will provide patients for whom treatment has previously been ineffective with a new, scientifically grounded option to explore.