Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.

Abstract

The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral Tcells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit Tcell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic Tcells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of Tcells, subsequently leading to aberrant metabolic and signaling pathways that drive Tcell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since Tcell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.