Digoxin Targets Central Carbon Metabolism and Remodels the Tumor Microenvironment

Cancer therapies targeting metabolism have been limited due to toxicity, compound availability, and efficacy. Therefore, strategies for targeting tumor-specific vulnerabilities remain highly desired. Digoxin, a widely used cardiac glycoside in humans, has been shown to exhibit antineoplastic properties. Using metabolomic approaches, we show that a primary consequence of digoxin treatment in tumor cells is disruption of central carbon metabolism via inhibition of the Na+/K+ ATPase, an enzyme that consumes a large portion of cellular ATP leading to globally altered energy demands when its activity is disrupted. Furthermore, in an immunocompetent mouse model of sarcoma, we show that digoxin targets these metabolic processes in both malignant and healthy tissue, particularly within cardiac tissue, while exhibiting tumor-specific cytotoxic activity. Single-cell RNA sequencing of 31,611 cells within the mouse sarcoma model demonstrates that acute digoxin treatment induces a shift in the tumor microenvironment, leading to transcriptional reprogramming of energy-generating processes in both tumor and immune cells. These results suggest that digoxin suppresses tumor growth by targeting central carbon in both tumor cells and the immune compartment, rendering it promising as an antitumor agent for metabolic therapeutic and immunomodulatory applications.