A sedentary lifestyle increases the risk of cancer, while regular exercise helps prevent it, improves survival, and boosts the effectiveness of anti-cancer therapies. Now, a study in mice shows that exercise helps fight cancer by changing gut bacteria to produce more formate—a compound that boosts the immune system’s ability to attack tumors. 

The findings, published in Cell, suggest that the gut microbiota plays a key role in the cancer-fighting benefits of exercise, highlighting formate as a potential target to boost cancer treatment.

Previous studies have found that exercise changes the gut microbiota, and other factors such as diet, probiotics, and antibiotics also affect cancer risk by altering gut bacteria. However, it’s unclear whether the way exercise changes the microbiota directly contributes to its cancer-fighting effects.

Catherine Phelps at the University of Pittsburgh School of Medicine in Pennsylvania and her colleagues investigated how exercise influences cancer by analyzing changes in the mice gut microbiota and their effect on antitumor immunity.

Exercise benefits

The researchers created a controlled treadmill exercise routine and then tested how well this exercise program helped fight melanoma tumors in healthy mice that were kept in a clean environment free from certain pathogens. They found that regular exercise reduced tumor growth and helped mice live longer. 

Exercise boosted the activity of specific immune cells called CD8 T cells, which attack tumors, but didn’t increase the number of these cells overall. Exercise also changed the types of bacteria present in the animals’ guts. 

When gut bacteria from mice that exercised were transferred to other mice, those animals also showed slower tumor growth and stronger immune responses. But when gut bacteria were removed with antibiotics, exercise no longer helped control tumor growth. The team also found that certain microbial metabolites, in particular a molecule called formate, was increased by exercise. Higher formate levels were linked to stronger immune responses against the tumor and slower tumor growth. 

Promising target

Giving mice formate helped slow tumor growth and boosted the immune system’s ability to fight cancer. This compound activates a key immune pathway in CD8 T cells, boosting their ability to fight tumors, the researchers found. 

By analyzing data from multiple studies in humans, the team also identified specific bacterial groups that increase formate production in people who respond well to anti-cancer treatment, similar to changes seen in mice that exercised. When gut bacteria from human donors with high formate levels were transferred to mice, those mice showed stronger immune responses and better tumor suppression compared to mice receiving gut bacteria from human donors with low formate levels. 

“Our findings […] identify formate as a promising metabolic target for improving cancer immunotherapy,” the authors say. The work, the add, could inform the development of therapeutic approaches that combine exercise and microbial metabolites to evaluate the antitumor efficacy of formate and similar molecules in people with cancer.