LXRβ pathway suppresses CD8+ T cell activation in ovarian carcinoma ascites.

Abstract Ovarian cancer (OC) is the deadliest gynecological malignancy, characterized by accumulating fluid (ascites) in the peritoneal cavity at the advanced stage. OC ascites exhibits immunosuppressive activity against various immune cells, including CD8 + T cells, through mechanisms not yet fully understood. Here, we show that OC ascites suppresses sterol regulatory element-binding protein (SREBP)-driven genes crucial for cholesterol biosynthesis while inducing liver X receptor β (LXRβ) targets facilitating cholesterol elimination in CD8⁺ T cells. This transcriptional reprogramming was accompanied by a failure to remodel the lipidome toward membrane-supportive phospholipids, promote free cholesterol accumulation, and increase plasma membrane order following T cell receptor (TCR) engagement. These defects coincided with blunted proximal TCR signal transduction, impaired TCR surface recycling, and reduced induction of the transcription factor Interferon Regulatory Factor 4 (IRF4), resulting in diminished CD8⁺ T cell activation and function. Targeted lipidomics identified enrichment of 27-hydroxycholesterol (27-HC) in OC ascites relative to non-malignant ascites. Adding 27-HC to the culture media recapitulated the suppressive phenotype and the associated SREBP/LXR transcriptional signature, suggesting that the 27-HC/LXR axis contributes to OC ascites-mediated CD8 + T cell suppression. Accordingly, pharmacological inhibition of LXRβ with the inverse agonist SR9243 partially restored CD8⁺ T cell activity and IRF4 expression in OC ascites. In turn, pharmacological activation of LXRβ with the agonist GW3965 phenocopied the suppression induced by OC ascites. These findings link OC ascites to impaired membrane order and TCR signaling in CD8⁺ T cells via a 27-HC/LXRβ axis, suggesting LXRβ antagonism may restore antitumor CD8 + T cell function in OC.