RORγ is a context-specific master regulator of cholesterol biosynthesis and an emerging therapeutic target in cancer and autoimmune diseases

Aberrant cholesterol metabolism and homeostasis in the form of elevated cholesterol biosynthesis and dysregulated efflux and metabolism is well recognized as a major feature of metabolic reprogramming in solid tumors. Recent studies have emphasized on major drivers and regulators such as Myc, mutant p53, SREBP2, LXRs and oncogenic signaling pathways that play crucial roles in tumor cholesterol metabolic reprogramming. Therapeutics such as statins targeting the mevalonate pathway were tried at the clinic without showing consistent benefits to cancer patients. Nuclear receptors are prominent regulators of mammalian metabolism. Their de-regulation often drives tumorigenesis. RORγ and its immune cell-specific isoform RORγt play important functions in control of mammalian metabolism, circadian rhythm and immune responses. Although RORγ, together with its closely related members RORα and RORβ were identified initially as orphan receptors, recent studies strongly support the conclusion that specific intermediates and metabolites of cholesterol pathways serve as endogenous ligands of RORγ. More recent studies also reveal a critical role of RORγ in tumorigenesis through major oncogenic pathways including acting a new master-like regulator of tumor cholesterol biosynthesis program. Importantly, an increasing number of RORγ orthosteric and allosteric ligands are being identified that display potent activities in blocking tumor growth and autoimmune disorders in preclinical models. This review summarizes the recent preclinical and clinical progress on RORγ with emphasis on its role in reprogramming tumor cholesterol metabolism and its regulation. It will also discuss RORγ functional mechanisms, context-specificity and its value as a therapeutic target for effective cancer treatment.