Role of protein regulators of cholesterol homeostasis in immune modulation and cancer pathophysiology

Abstract Cholesterol metabolism and homeostasis have emerged as important factors governing various aspects of cancer biology. Clinical associations between circulating cholesterol and poor prognosis, or use of cholesterol-lowering medication and improved prognosis have been noted for several different solid tumors. Mechanistically, cholesterol has many different direct and indirect effects on cancer cells themselves, but is also critically involved in shaping the function of other cells of the tumor microenvironment, especially immune cells. There are two major feedback loops regulating cholesterol homeostasis. Here, we highlight the major proteins involved in the so-called oxysterol – bile acid feedback loop and discuss how each one has been implicated in cancer biology. We focus on roles within the immune system with implications for cancer. Given that many of these proteins are enzymes or nuclear receptors, both of which are amenable to small molecule intervention, we posit that this axis may represent a promising area for therapeutic intervention.