Over the past few years, researchers have been developing an anticancer therapy strategy that helps a patient’s own immune system destroy tumors. The monoclonal antibody treatment prevents tumor cells from sending signals that depress a patient’s immune system. By preventing tumor cells from interfering with proper immune system functioning, the patient’s own immune cells can identify unique antigens—which can be thought of as chemical features—on cancer cells and target them for destruction. The antibody drugs, called immune checkpoint inhibitors, have had variable responses in lung cancer patients, however. A team led by Sergio A. Quezada of University College London and Charles Swanton of the Francis Crick Institute set out to discover why. They found that if a patient’s tumor cells have antigens that are all very similar—that is, “clonal”—then the patient’s immune system can easily identify malignant cells and destroy them. But when tumor cells have a mixed collection of antigens, the patient’s immune system isn’t as adept at its search-and-destroy mission (Science 2016, DOI: 10.1126/science.aaf490). The work could help clinicians identify which patients will benefit most from anticancer treatments that focus on activating the immune system.