Deoxysphingolipids activate cGAS-STING in colon cancer cells and enhance tumor immunity

Deoxysphingolipids (deoxySLs) are a class of non-canonical sphingolipids that can adversely impact mitochondrial function. Mitochondrial disruption can activate the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING1) 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 through mutation of SPT in cells and feeding a high alanine diet to mice exerted similar effects, including immune-mediated tumor growth suppression. Work conducted in multiple in vitro systems identified deoxySLs as key triggers of cGAS-STING1 activation, an effect mediated by mitochondrial release of double-stranded DNA resulting from mitochondrial stress. Collectively, these findings provide the first evidence that deoxySLs can drive antitumor immunity and identify a previously unrecognized metabolic strategy for cancer therapy.