A groundbreaking new study reveals that exercise rewires the microbiome to supercharge the immune system’s cancer-killing cells. The secret weapon seems to be a tiny molecule made by gut microbes called formate. The study has shown that this formate can shrink tumors and boost the power of immunotherapy, and could even be used as a supplement for treatments.

Muscles Are Your Anti-cancer Friend

For years, researchers have observed that physically active people tend to do better against cancer. Their tumors grow more slowly and patients often respond more effectively to drugs. A key part of this is maintaining a healthy weight and staying fit. But that’s not all of it. Something else is at play, and researchers weren’t sure what.

Marlies Meisel, an immunologist at Pitt and researcher at UPMC Hillman Cancer Center, wanted to connect the dots. Her team suspected the gut microbiome — our inner universe of trillions of bacteria — might play a hidden role. After all, exercise is known to shift which microbes thrive in the gut, so it seemed like a good place to start.

To find out, Meisel’s lab, led by graduate student Catherine Phelps, gave mice an aggressive form of melanoma. Half the mice ran on tiny treadmills for four weeks. The other half stayed sedentary.

The benefits were striking. Exercised mice had smaller tumors and lived longer. But when the team gave the same cancer to germ-free mice (born and raised without any gut microbes) or treated regular mice with antibiotics that wiped out their gut bacteria, the benefit of exercise vanished. It was like they weren’t doing anything at all. This is as close to causality as you can get with this type of complex impact.

“We already knew that exercise increases the effectiveness of cancer immunotherapies, and we separately knew that exercise changes the microbiome in mice and humans,” said senior author Marlies Meisel, assistant professor of immunology, School of Medicine, and affiliated with UPMC Hillman Cancer Center. “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. These findings open the door to new therapeutic strategies targeting the microbiome.”   

What’s Up with Formate?

The problem, however, is that figuring out how gut bacteria help is only half of the problem. Gut bacteria produce thousands of different molecules, and it’s hard to tell which one is helping the immune system.

To narrow it down, the team turned to machine learning. Their algorithm flagged a likely culprit: formate, a compound produced by certain gut microbes in higher quantities after exercise.

So they went to test it. They gave mice formate directly, and it mimicked the effects of exercise, shrinking tumors and boosting survival in multiple cancer types. In particular, formate appeared to act by enhancing CD8 T cells, the immune system’s elite cancer-killers. Even more promising: in mice treated with checkpoint inhibitor immunotherapy, formate made the treatment more effective.

“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 nonresponders.”

From Mice to Humans

Of course, just because it works in mice doesn’t necessarily mean the same works in humans. To investigate this, the team studied blood samples from 19 patients with advanced melanoma undergoing immunotherapy. Those with high levels of formate in their blood had better progression-free survival (meaning their cancer stayed stable longer).

Then, they did one more thing. Then, they performed fecal transplants from these patients into mice with melanoma. Mice that received stool from high-formate donors had stronger immune responses and better tumor control.

Fecal microbial transplants (FMT) is already being explored as a therapy to improve immunotherapy outcomes. But it wasn’t clear why some “super donor” stool leads to better outcomes.

“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.”

This research suggests formate might one day be given as a supplement to boost cancer immunity. Or, perhaps more simply, patients could be prescribed a tailored exercise regimen — not just for general health, but to reshape their microbial ecosystem. There are still many uncertainties, but it’s a promising avenue.

Now, Meisel and her team are investigating whether exercise-induced changes to the gut microbiome could also help in other diseases like autoimmune disorders.

The study was published in Cell.