Over the past decade, harnessing the power of a patient’s own immune system for the treatment of cancer has been a major medical breakthrough. By using drugs to block inhibitory signals on immune cells, these medicines help “release the brakes” allowing them to kill cancer cells. One of these drugs is an antibody directed against a protein called CTLA-4. So transformative to the care of patients with melanoma and other cancers, the investigators who initially described such pathways were recently awarded the Nobel Prize. While these therapies have been lifesaving for many, they still fail to benefit the majority of patients receiving them. The reason for this lack of activity in some remains poorly understood. We recently uncovered a mechanism of how this may happen, in that cancers develop another “checkpoint” preventing the activity of anti-CTLA-4 antibodies at the tumor site. This checkpoint, called FcyRIIB, becomes increased in tumors and limits the ability of anti-CTLA-4 antibodies to deplete an important cell type contributing to the suppression of anti-cancer immunity. These studies will investigate this pathway in pre-clinical models and patient specimens, with the goal of using this knowledge to translate improved anti-CTLA-4 antibodies into the clinic.