Grant: Operating Grant: TRANSCAN-3

Immunotherapy is a promising cancer treatment that helps the body's immune system fight tumors. However, it only works well for a small number of patients, and doctors still don't fully understand why. One potential way to improve its success is by combining it with radiation therapy (RT), which may help activate the immune system. But in many clinical trials, this combination has shown limited benefits, suggesting we need better ways to make it more effective. Our research explores how cancer cell metabolism-the way cancer cells use energy-and the bacteria living in the gut (the microbiota) influence how patients respond to these treatments. As part of a large European research project (ONco-Energetics_OFF), we studied different types of cancer cells to see how flexible their metabolism is when stressed. We found that how cancer cells manage their energy is closely linked to how well they respond to immunotherapy. We also studied gut bacteria and metabolism in the blood of cancer patients receiving CAR T cell therapy, a form of personalized immunotherapy. We discovered that patients who responded well had a certain type of helpful gut bacteria and lower levels of specific metabolic byproducts. In mouse models, adding this bacteria alongside CAR T cell therapy improved tumor control. Together, these findings point to new ways to boost the effectiveness of cancer treatments by targeting metabolism and the gut microbiome-helping more patients benefit from cutting-edge therapies.