Gut Microbes Key in Exercise's Cancer-Fighting Effect

A new study from the University of Pittsburgh shows for the first time how exercise improves cancer outcomes and enhances response to immunotherapy in mice by reshaping the gut microbiome.

The research, published today in the journal Cell, found that these benefits are driven by a specific compound called formate, which is produced by gut bacteria in exercised mice and was also associated with better outcomes in patients with melanoma. 

Lead author Catherine Phelps, a Graduate Program in Microbiology and Immunology student in Meisel’s lab, and the research team started by comparing mice that had completed four weeks of regular exercise to those that remained sedentary. The exercised animals had smaller tumors and better survival when challenged with an aggressive form of melanoma. But these benefits disappeared when they used germ-free rodents or treated the mice with antibiotics that killed off their gut microbiome.

Next, the researchers showed that it was compounds, or metabolites, produced by bacteria rather than the bacteria themselves, driving these effects. They then used a machine learning tool called SLIDE that analyzes metabolic pathways to identify microbiota-derived formate as the key player.

Additional experiments showed that formate acts by enhancing the potency of CD8 T cells, the chief cancer-killing battalion of the immune system. In mouse models of melanoma, adenocarcinoma and lymphoma, daily oral formate greatly inhibited tumor growth and improved survival. Formate also enhanced the efficacy of immune checkpoint inhibitor immunotherapy in mice with melanoma. 

“It’s really exciting to identify a specific bacterial metabolite that mimicked the effects of exercise in mice,” said Meisel. “In the future, formate could potentially be investigated as an adjuvant therapy to improve the efficacy of immune checkpoint inhibitors in non-responders.”

To investigate the relevance of formate in humans, Meisel and her team looked at advanced melanoma patients who received immune checkpoint inhibitor therapy. Those with high levels of formate in their blood had better progression-free survival than patients with low levels of the metabolite.

And when they performed fecal microbial transplants (FMT) from people with either high or low levels of formate into mice with aggressive melanoma, strikingly, the animals that received the high formate fecal transplant had enhanced T cell activity and better tumor control. 

FMT is already being explored as a therapy to improve immunotherapy outcomes in non-responders. But why some “super donor” stool leads to better outcomes is not entirely clear. 

“We want to describe metabolic biomarkers to identify FMT super donors because that’s really a black box,” said Meisel. “Currently everyone focuses on bacterial species, but our research suggests that it’s not just about which microbes are present, but what they are doing and which metabolites they are producing.”

Now, Meisel and her team are investigating whether exercise-induced changes to the gut microbiome could play a role in other diseases such as autoimmune disorders. They are also interested in understanding the mechanisms by which exercise influences the microbiome in the first place. 

Reference: Phelps CM, Willis NB, Duan T, et al. Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. Cell. 2025;0(0). doi: 10.1016/j.cell.2025.06.018

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