Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity

Deoxysphingolipids (deoxySLs) are a class of non-canonical sphingolipids that can adversely impact mitochondrial function. Mitochondrial DNA release resulting from mitochondrial disruption can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and in turn, promote antitumor immunity. Here, we investigated whether inducing deoxySL accumulation in colon cancer cells drives immune-specific, antitumor effects. We show that depleting serine increased deoxySLs and enhanced immune cell infiltration in colon tumors, in parallel with suppressing tumor growth. Elevating tumor deoxySL levels in mice through mutation of serine palmitoyltransferase and feeding a high alanine diet exerted similar effects, including immune-mediated tumor growth suppression. Work conducted in multiple in vitro systems identified deoxySLs as key triggers of cGAS-STING activation, an effect mediated by the release of mitochondrial DNA under mitochondrial stress. Collectively, these findings demonstrate that deoxySLs drive antitumor immunity and identify a previously unrecognized metabolic strategy for cancer therapy.