Targeting ACAT1 for Precision Chemo-Immunoprevention in Lung Cancer

Lung cancer (LC) is a leading cause of cancer-related deathworldwide, and altered cholesterol metabolism is a hallmark of cancer cells. Acyl-CoA:cholesterol acyltransferase 1(ACAT1), or Sterol O-acyltransferase 1 (SOAT1), isa key cholesterol esterification enzyme. Its overexpression promotes tumorprogression by accumulating cholesterol esters. Inhibition of ACAT1 also potentiatesCD8+ T cells medicated anti-tumor immunity by increasing plasma membranecholesterol level. This study, as the first of its kind, shows the ACAT1/SOAT1 overexpressioncorrelates with poor prognosis in early-stage lung adenocarcinoma (LUAD) patients.Long-term treatment with ACAT1 inhibitor avasimibe suppresses tumorigenesis inboth Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growthfactor receptor (EGFR) mutation-induced LC mouse models without overttoxicity. ACAT1 inhibition reduces tumor cell proliferation, migration, andinvasion and causes G0/G1 cell cycle arrest, while boosting CD8+ T cells'effector function and memory phenotype. Single-cell RNA sequencing reveals thatACAT1 inhibition downregulates cholesterol biosynthesis and central carbon andnitrogen metabolism pathways in tumor cells, while upregulating genes relatedto oxidative phosphorylation and fatty acid oxidation in CD8+ T cells. Finally, avasimibe improves the efficacy of a human EGFR vaccine in preventing LCprogression. These novel findings suggest potential strategies for cancer preventionand therapy.