Impact of Gut Microbes and Exercise on Cancer Immunotherapy Efficacy

In a groundbreaking study published on July 10, 2025, in the journal *Cell*, researchers from the University of Pittsburgh have demonstrated a significant link between exercise, gut microbiota, and enhanced responses to immunotherapy in cancer treatment. The study, led by graduate student Catherine Phelps in the Microbiology and Immunology Graduate Program, reveals that exercise influences the gut microbiome, producing a specific metabolite known as formate. This compound has been found to play a crucial role in improving cancer outcomes and augmenting the efficacy of immunotherapy, particularly in mouse models of melanoma.

The research involved comparing the cancer responses of two groups of mice: those that underwent four weeks of regular exercise and sedentary counterparts. Findings indicated that the exercised mice exhibited smaller tumors and improved survival rates when subjected to an aggressive melanoma strain. However, these benefits were negated when the researchers utilized germ-free rodents or treated the mice with antibiotics, suggesting that the gut microbiome itself, along with its metabolites, is instrumental in these processes.

The identification of formate as a key metabolite was facilitated through advanced machine learning tools, specifically the SLIDE algorithm, which analyzes metabolic pathways. Subsequent experiments revealed that formate enhances the activity of CD8 T cells—crucial components of the immune system responsible for targeting and destroying cancer cells. In various mouse models, oral administration of formate significantly reduced tumor growth and bolstered survival rates. Notably, formate also improved the effectiveness of immune checkpoint inhibitors in melanoma models, indicating its potential as a supplemental therapy in cancer treatment.

Catherine Meisel, a leading researcher in the study, expressed excitement over the discovery of a specific bacterial metabolite that can replicate the beneficial effects of exercise in mice. She emphasized the possibility of exploring formate as an adjunct therapy to improve responses in patients who do not initially respond to immunotherapy. The study also analyzed data from advanced melanoma patients undergoing immune checkpoint inhibitor therapy, revealing that those with elevated blood levels of formate experienced better progression-free survival rates compared to those with lower levels.

Fecal microbial transplants (FMTs) from patients with varying levels of formate were administered to mice with aggressive melanoma. Results showed that the mice receiving transplants from high formate donors had enhanced T cell activity and superior tumor control, suggesting that the presence of certain metabolites can significantly influence therapeutic outcomes.

Despite these promising findings, researchers aim to uncover the mechanisms that dictate why specific donor fecal matter leads to better immunotherapy responses. Meisel indicated a pressing need to identify metabolic biomarkers to pinpoint effective FMT donors, highlighting that current research predominantly focuses on bacterial species rather than their metabolic activities.

Future investigations will examine whether exercise-induced changes in the gut microbiome could also positively impact autoimmune disorders and explore the underlying mechanisms of how exercise influences the microbiome. This research sheds light on the intricate relationship between lifestyle factors, microbiota, and cancer treatment, paving the way for innovative therapeutic strategies in oncology.

**References**: 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.