An Immunometabolic Route for Activating cGAS/STING to Drive Anticancer Immunity.

The cGAS/STING pathway is a crucial immune activator in cancer biology, triggering innate immunosurveillance against tumors by sensing and reacting to endogenous mitochondrial DNA (mtDNA). In this issue of Cancer Research, research by Saha and colleagues highlights the significant impact of serine deprivation on this pathway, thereby unveiling its potential for anticancer therapy. Serine is essential for cellular metabolism and influences tumor growth and immune responses. Depriving cells of serine caused mitochondrial dysfunction and the release of mtDNA into the cytosol, activating the cGAS/STING pathway and inducing type I IFN responses. In mouse models, serine deprivation enhanced antitumor immunity, with increased tumoral immune infiltration, including CD4+/CD8+ T cells and type I IFN responses. Clinically, a genetic signature indicative of lower serine enrichment in colorectal cancer patients correlated with immune activation and improved survival. Furthermore, combining serine deprivation with PD1 blockade significantly reduced tumor volume and led to long-term immunity in mice, suggesting that serine depletion enhances the efficacy of immune checkpoint blockade. These findings propose serine deprivation as a promising strategy to boost antitumor immunity and improve cancer patient outcomes. See related article by Saha et al., p. 2645.