In a new study, researchers have uncovered how exercise might help the immune system fight cancer: by changing the gut microbiome in a way that boosts production of a compound called formate. This microbial byproduct, the study shows, plays a key role in helping immune cells slow tumor growth—at least in mice.
The study, published in Cell, has revealed a striking biological chain reaction in mice: exercise alters the gut microbiome, boosting production of formate, which in turn supercharges the body’s immune defenses against tumors. The discovery may help explain why exercise enhances the effectiveness of immunotherapy.
“We already knew that exercise increases the effectiveness of cancer immunotherapies,” said Marlies Meisel, Ph.D., senior author of the study and assistant professor of immunology at the University of Pittsburgh. “This study connects those dots by showing how exercise-induced changes in the gut microbiome boost the immune system and enhance immunotherapy efficiency via formate.”
A Chain Reaction from Treadmill to Tumor
The researchers began by asking a simple question: why does exercise help certain cancer treatments succeed? Immunotherapy drugs called immune checkpoint inhibitors (ICIs) unshackle the immune system to attack cancer cells. However, ICIs work for some people but not others. Exercise has been shown to improve their odds, but the mechanism was a mystery.
To explore this, lead author Catherine Phelps and colleagues trained mice to run on treadmills daily for four weeks. These mice, when later implanted with melanoma tumors, showed slower tumor growth and improved survival compared to their sedentary counterparts.
But when scientists eliminated the mice’s gut microbes using antibiotics or used germ-free mice, those benefits vanished.
“When we removed microbes from the equation, exercise no longer had any effect on cancer outcomes in mice,” Phelps said. “We were surprised to see such a clear signal that the beneficial effects of exercise were due to the microbiome.”
That realization set off a deeper investigation. The team transplanted fecal matter—yes, poop— from exercised mice into sedentary ones. Remarkably, the tumor-suppressing effects transferred along with the microbes. Mice receiving these transplants lived longer and mounted a stronger immune attack on their tumors.
The culprit, it turned out, wasn’t the bacteria themselves, but what they were making.
Formate: A Microbial Metabolite Hitman
Using machine learning and metabolomic analysis, the researchers identified the defining molecule among the thousands of compounds produced by gut microbes: formate.
Formate is a one-carbon molecule naturally made by certain bacteria. In this study, it emerged as the linchpin of the immune-boosting effect. Exercise increased levels of formate in the mice’s gut and bloodstream. Mice treated with formate alone, even without exercise, exhibited reduced tumor growth and better survival.
Formate appeared to strengthen CD8 T cells, the immune system’s most lethal cancer-fighting force. These cells became more active, proliferated faster, and produced more of the chemicals that kill tumor cells.
In multiple mouse models—including melanoma, adenocarcinoma, and lymphoma—oral doses of formate mimicked the cancer-fighting benefits of exercise. When combined with checkpoint inhibitors, the effects were even stronger.
“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.”
Connecting the Dots in Humans
Could this effect translate to people?
To find out, the team analyzed blood samples from melanoma patients undergoing immunotherapy. Those with higher levels of formate had longer progression-free survival than those with lower levels.
They also took fecal samples from healthy adults and sorted them by formate content. Mice that received fecal transplants from high-formate donors developed smaller tumors and mounted a stronger T cell response. The “super donor” samples, rich in formate-producing microbes, seemed to pass on their anti-cancer edge.
This could help demystify a puzzling aspect of cancer immunotherapy. Some patients respond dramatically to treatments like checkpoint inhibitors, while others don’t. Fecal transplants from select donors—sometimes called “super donors”—have shown promise in improving response. But until now, no one knew what made a donor “super.”
“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.”
A New Path for Cancer Treatment?
Of course, this discovery doesn’t mean running a few miles will cure cancer overnight. But it underscores the powerful, and still often underappreciated, influence of the microbiome, especially as a mediator of how lifestyle affects disease.
It also opens the door to new treatments. Could formate be given as a supplement alongside immunotherapy? Could diets or probiotic regimens enhance formate-producing microbes in patients? Might cancer treatment someday involve prescribing time on a treadmill?
There are caveats. The research, while rigorous, was conducted on mice. Human biology is messier and more complex. The exact microbes that produce formate in humans remain to be identified. And the interplay between formate, the immune system, and tumor cells will need further untangling.
Still, the implications are significant. As scientists continue to hunt for ways to make immunotherapy work better, they may want to look not just in the lab, but also in the gym—and in the gut.
“Our findings underscore the critical role of the microbiota in mediating exercise-driven enhancement of ICI therapy,” the authors write, “and identify formate as a promising metabolic target for improving cancer immunotherapy.”
