A groundbreaking study published in Cell Metabolismoffers compelling evidence that the benefits of exercise for cancer patients extend far beyond general wellness. It uncovers a precise biological mechanism by which physical activity boosts the immune system’s ability to fight cancer, providing molecular support for what many clinicians have observed anecdotally for years.

The research shows that exercise significantly enhances the effectiveness of cancer immunotherapies, particularly immune checkpoint inhibitors (ICIs), by strengthening CD8 T cell–mediated antitumor immunity.

Central to this effect is the gut microbiota. In mice, fecal transplants from exercised donors improved antitumor immune responses and slowed tumor growth. When these microbes were removed—either through broad-spectrum antibiotics or by using germ-free mice—the protective effect of exercise disappeared entirely. This clearly demonstrated that a functioning microbiota is essential for exercise to enhance immune responses against cancer.

At the heart of this microbiota-mediated effect is a single metabolite: formate.

Exercise was found to stimulate microbial one-carbon metabolism in the gut, significantly increasing formate levels in the intestines, bloodstream, and, to a lesser extent, tumor tissue. These higher formate levels correlated with stronger Tc1 immune responses and slower tumor progression. Remarkably, oral supplementation of formate alone reproduced many of the benefits of exercise in multiple mouse cancer models—including melanoma, adenocarcinoma, and lymphoma—and enhanced the efficacy of anti-PD-L1 therapy. However, these effects required an intact immune system; formate had no impact in immunodeficient mice, emphasizing that its benefits are mediated through adaptive immunity and CD8 T cells specifically.

The researchers also found that formate enhances the STAT1–IRF8 axis—a pathway crucial for the differentiation of CD8 T cells into potent tumor-killing Tc1 cells.

These findings are not limited to animal models. In human data, higher abundance of the bacterial enzyme pyruvate formate lyase (pfl)—involved in microbial formate production—was associated with better responses to anti-PD-1 immunotherapy in melanoma patients. Additionally, higher serum formate levels in patients correlated with longer progression-free survival. Transferring fecal microbiota from high-formate–producing human donors into mice conferred significantly better tumor control and immune activation, suggesting that formate may serve as a biomarker for identifying patients likely to benefit from immunotherapy—and possibly for selecting “super-donors” in fecal microbiota transplant strategies.

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