ACAT1 catalyzes the final step of mitochondrial beta-oxidation, cleaving medium- to long-chain 3-oxoacyl-CoAs into acetyl-CoA and shortened fatty acyl-CoA molecules. The enzyme also catalyzes the reversible condensation of two acetyl-CoA molecules into acetoacetyl-CoA, playing a central role in ketone body metabolism. Beyond fatty acid catabolism, ACAT1 regulates cholesterol esterification in macrophages and influences histone acetylation levels that control gene expression programs. Loss-of-function mutations cause 3-ketothiolase deficiency, characterized by episodic ketosis, metabolic acidosis, and in severe cases neurological damage 12. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant (LOEUF=0.80); this is distinct from clinical pathogenicity in disease contexts, as 213 pathogenic/likely pathogenic ClinVar variants have been documented. Recent evidence reveals ACAT1's broader immunometabolic roles: ACAT1 inhibition enhances CD8+ T-cell antitumor immunity by increasing plasma membrane cholesterol and T-cell receptor signaling 3, and ACAT1 loss in tumor cells promotes tertiary lymphoid structures and sensitizes non-small cell lung cancer to anti-PD-1 immunotherapy 4. The ACAT inhibitor avasimibe, previously tested clinically for atherosclerosis, shows promising efficacy in cancer immunotherapy, either as monotherapy or combined with anti-PD-1 antibodies 3.