The Na+/K+ ATPase Regulates Glycolysis and Defines Immunometabolism in Tumors

Cancer therapies targeting metabolism have been limited due to a lack of understanding of the controlling properties of vulnerable pathways. The Na+/K+ ATPase is responsible for a large portion of cellular energy demands but how these demands influence metabolism and create metabolic liabilities are not known. Using metabolomic approaches, we first show that digoxin, a cardiac glycoside widely used in humans, acts through disruption to central carbon metabolism via on target inhibition of the Na+/K+ ATPase that was fully recovered by expression of an allele resistant to digoxin. We further show in vivo that administration of digoxin inhibits glycolysis in both malignant and healthy cells, particularly within clinically relevant cardiac tissue, while exhibiting tumor-specific cytotoxic activity in an allografted soft tissue sarcoma. Single-cell expression analysis of over 31,000 cells within the sarcoma shows that acute Na+/K+ ATPase inhibition shifts the immune composition of the tumor microenvironment, leading to selective transcriptional reprogramming of metabolic processes in specific immune cells thus acting both through tumor cell autonomous and non-autonomous (e.g. macrophage) cells. These results provide evidence that altering energy demands can be used to regulate glycolysis with specific cell-type specific consequences in a multicellular environment.