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

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 of intratumoral cells. Low cholesterol levels inhibit T-cell proliferation and cause autophagy mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations of the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXR depletion in CAR-T cells led to improved antitumor function against solid tumor. Comparative gene expression profiling analysis of RNA-seq data for SCAP CKO mouse T cells, in vitro/intratumoral CAR-T cells, RO 48-8071/RGX-104/GW3965 treated CAR-T cells and 27-HC treated CAR-T cells,