PFKFB3 and breast cancer: Pharmacologic inhibition of PFKFB3 imposed additional constrains on glucose utilization and significantly enhanced the antitumor efficacy of CDK4/6 inhibition in PDX models.<h4>Conclusions</h4>CDK4/6 inhibition rewires glucose metabolism in ER + breast cancer by increasing glycolytic flux while limiting downstream glucose utilization, resulting in heightened reliance on regulated glycolytic control to maintain metabolic homeostasis during cell cycle arrest.