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Jul 9, 2025
We already knew that exercise boosts the effectiveness of cancer immunotherapies and that it alters the gut microbiome said senior author Dr. Marlies Meisel assistant professor of Immunology at Pitt and researcher at UPMC Hillman Cancer Center. This study connects those dots showing how exercise-induced microbiome changes enhance immune response and improve immunotherapy through formate paving the way for new microbiome-targeted therapies.
Lead author Catherine Phelps a graduate student in Meisel’s lab and her team compared mice that exercised regularly for four weeks to sedentary controls. The active mice had smaller tumors and improved survival against aggressive melanoma. However when the gut microbiome was eliminated either by using germ-free mice or antibiotics the exercise-related benefits vanished.
In the next phase of their study the researchers discovered that it wasn’t the bacteria themselves but the metabolites they produce that were responsible for the cancer-fighting effects. Using a machine learning tool called SLIDE to analyze metabolic pathways they identified formate a compound generated by gut microbes as the key driver.
It’s incredibly exciting to pinpoint a specific bacterial metabolite that replicates the benefits of exercise said Dr. Meisel. Formate has the potential to be explored as an add-on therapy to increase immunotherapy success in patients who don't initially respond.
To assess its relevance in humans the team analyzed blood samples from melanoma patients undergoing immunotherapy. They found that individuals with higher blood levels of formate had better progression-free survival. Additionally fecal microbial transplants (FMT) from these high-formate patients into mice led to stronger T cell responses and better tumor control compared to transplants from low-formate donors.
We aim to identify metabolic markers to pinpoint ‘super donors for FMT Meisel said. Rather than just focusing on which bacterial species are present our research shows it’s crucial to understand what the microbes are actually doing especially which metabolites they’re producing.
Moving forward Meisel's team plans to explore whether exercise-induced microbiome shifts may benefit other conditions such as autoimmune diseases. They’re also working to unravel exactly how exercise influences the microbiome in the first place.