Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity. [Display omitted] •Squalene epoxidase (SQLE) blockade inhibits β-glucan-induced trained immunity in macrophages•SQLE produces reactive oxygen species (ROS) in trained macrophages to promote glycolysis•SQLE-catalyzed 24(S),25-epoxycholesterol activates LXR to reprogram chromatin accessibility•SQLE is required for interferon production in trained macrophages to boost antitumor activity Liu et al. show that trained immunity in macrophages requires SQLE-catalyzed squalene epoxidation, which not only produces 24(S),25-epoxycholesterol for LXR activation and ensuing reprogramming of histone modification and chromatin accessibility but also generates ROS for glycolytic induction, extending a non-classical function of SQLE in regulating trained immunity.