Exercise Enhances Cancer Immunotherapy by Modifying Gut Microbiome

A groundbreaking study from the University of Pittsburgh reveals how exercise significantly improves cancer outcomes and enhances the efficacy of immunotherapy in murine models by reshaping the gut microbiome. Published in the journal *Cell* on July 9, 2025, the research illustrates that exercise leads to an increase in a specific compound, formate, produced by gut bacteria, which correlates with improved responses to cancer treatment in both mice and melanoma patients.

The study, led by Dr. Marlies Meisel, an assistant professor in the Department of Immunology at the University of Pittsburgh School of Medicine, and graduate student Catherine Phelps, aimed to connect the previously established effects of exercise on cancer treatments and microbiome alterations. "We already knew that exercise increases the effectiveness of cancer immunotherapies, and we separately knew that exercise changes the microbiome in mice and humans. 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," Dr. Meisel stated.

In their experimental design, the researchers compared two groups of mice: those that engaged in four weeks of regular exercise and those that remained sedentary. The exercise group exhibited reduced tumor sizes and improved survival rates when challenged with an aggressive form of melanoma. However, these benefits were nullified in germ-free rodents or those treated with antibiotics, indicating that the gut microbiome plays a crucial role in mediating these effects. "When we removed microbes from the equation, exercise no longer had any effect on cancer outcomes in mice," Phelps noted, emphasizing the pivotal role of the microbiome.

The study further identified formate as the key metabolite responsible for the beneficial effects of exercise. Using advanced machine learning techniques, the research team discovered that formate enhances the effectiveness of CD8 T cells, which are vital to the immune response against tumors. In various mouse models of melanoma, adenocarcinoma, and lymphoma, the administration of daily oral formate led to significant tumor growth inhibition and improved survival rates. Furthermore, formate was shown to amplify the efficacy of immune checkpoint inhibitor therapies in melanoma models.

To assess the relevance of these findings in human subjects, Dr. Meisel's team analyzed data from advanced melanoma patients undergoing immune checkpoint inhibitor treatments. They found that patients with elevated blood levels of formate experienced better progression-free survival rates compared to those with lower levels. In a groundbreaking experiment involving fecal microbial transplants (FMT), mice receiving transplants from high formate donors exhibited enhanced T cell activity and superior tumor control.

Dr. Meisel elaborated on the implications of their findings, stating, "It's really exciting to identify a specific bacterial metabolite that mimicked the effects of exercise in mice. In the future, formate could potentially be investigated as an adjuvant therapy to improve the efficacy of immune checkpoint inhibitors in non-responders." This research opens new avenues for therapeutic strategies targeting microbial metabolites to enhance cancer treatment outcomes.

Looking ahead, Dr. Meisel and her team aim to explore the potential of exercise-induced changes in the gut microbiome in relation to other diseases, such as autoimmune disorders. They are also focused on elucidating the mechanisms through which exercise influences the microbiome, which remains an area ripe for investigation. This study not only enhances the understanding of cancer treatment but also underscores the intricate relationship between exercise, microbiome health, and immune response, paving the way for innovative cancer therapies in the future.

The study can be referenced as: Phelps, C. M., et al. (2025). Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. *Cell*. doi.org/10.1016/j.cell.2025.06.018.