RORα Regulates Cholesterol Metabolism of CD8⁺ T Cells for Anticancer Immunity

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8⁺ T cells by attenuating NF-kB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8⁺ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-kB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-kB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-kB signaling controls the balance of cholesterol metabolism in CD8⁺ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.