Immune checkpoint inhibitor (ICI) immunotherapies, which harness and enhance the human body’s own defense mechanisms to kill cancer cells, have revolutionized the treatment of solid cancers by changing the prognosis for many patients, improving their quality of life and offering long-lasting remission. But beyond unleashing the immune system to attack tumors, these therapies can also spur assaults on healthy organs called “immune-related adverse events” (irAEs), which are increasingly seen as the Achilles’ heel of such therapy.  To date, nearly every human organ system has been reported as affected by irAEs with a wide spectrum of severity, ranging from minor rashes and fevers to severe gastrointestinal complications and deadly heart inflammation problems. Dr. Villani’s research program at MGH works towards understanding why and how these irAEs occur in cancer patients by analyzing patient samples using state-of-the-art genomic technologies and integrative immunological approaches. The ultimate goal is to identify therapeutic solutions to prevent or better clinically manage irAEs without reducing the lifesaving potential of immunotherapy, by identifying culprit cellular and/or molecular components that could be therapeutically targeted through ‘primary prevention’ screening test approach, or after the onset of irAEs. Collectively, the research program embodies a true bench-to-bedside evaluation of new disease entities, and the outcomes have the potential to greatly benefit patient care and improve management of all cancer types treated with immune checkpoint inhibitor therapies.