Immunotherapy has been remarkably successful in the treatment of melanoma, but not all patients benefit from therapy and its effects is in most cases temporary, followed by development of resistance. Immunotherapy largely relies on active and persistent T cells, and thus elucidating regulatory mechanisms of T cell function is of paramount importance to the development of more effective immune therapies. CDK4 and CDK6 are closely related kinases that are known to control cell cycle progression. Recent studies reported that CDK4/6 inhibitors unexpectedly stimulate T cells and tumor immunity, but the underlying mechanisms remain incompletely understood. Efforts to translate these findings to the clinic have been disappointing thus far, with the combination of CDK4/6 inhibitors with immune checkpoint blockade showing modest efficacy and increased toxicities in clinical trials. Since CDK4/6 inhibitors both activate certain function of T cells, but they also block their proliferation, the path to clinically exploit the immunostimulatory properties of these drugs remains unclear. The overall objective of this application is to elucidate mechanisms underlying the immunostimulatory properties of CDK4/6 inhibitors, and to leverage those properties to potentiate melanoma immunotherapy.