To cycle or fight—CDK4/6 inhibitors at the crossroads of anticancer immunity

Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor–positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy.