Checkpoint receptors in the immune synapse play a central role in regulating the immune response against tumors and are emerging as powerful targets in cancer immunotherapy. Enhancement of the patient’s own immune response against the tumor is achieved by using therapeutic antibodies to either block inhibitory checkpoints that limit the anti-tumor immune response, or activate stimulatory checkpoints that enhance immune responses. Our recent studies identified unexpected FcγR-dependent mechanisms induced by several checkpoint antibodies to mediate their optimal anti-tumor activity. These studies highlighted the importance of the antibody’s Fc domain and identified their optimal Fc scaffold. We are now studying the role of FcγR pathways in the tumor microenvironment during immunotherapy and characterizing interactions with checkpoint control antibodies. For maximum clinical relevance we are studying human antibodies in mice humanized for FcγRs and the targeted checkpoint receptors. We are exploring strategies to enhance the identified FcγR pathways and aim to create 2nd generation antibodies with improved activity.