Forced expression of UCP1 counteracts the compromised activity of NK cells in the tumor microenvironment

Uncoupling protein 1 (UCP1) is a mitochondrial inner membrane protein that mediates non-shivering thermogenesis in brown adipose tissue. Natural killer cells are key effectors of antitumor immunity but are impaired in the tumor microenvironment. Here we show that UCP1 is downregulated in tumor-infiltrating NK cells (TINKs) from colorectal cancer patients and tumor-bearing mice and correlates with impaired effector function. Natural killer cell-specific UCP1 ablation accelerates tumor growth and reduces tumor infiltration. Transforming growth factor β1 and hypoxia repress UCP1 transcription through C/EBPβ downregulation. UCP1 deficiency increases CD36/FABP4-mediated fatty acid uptake and alters mitochondrial respiration, accompanied by mitochondrial damage, mitochondrial DNA release, NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, and pyroptosis. Enforced UCP1 expression prevents tumor microenvironment-induced pyroptosis and maintains antitumor activity in murine models and patient-derived organoids. Genetically modified expression of UCP1 in NK cells is a potential therapy for patients with tumors. UCP1 loss in tumor-infiltrating NK cells drives CD36/FABP4-dependent fatty acid oxidation, mitochondrial DNA release and NLRP3-mediated pyroptosis. Restoring UCP1 preserves NK cell function and antitumor activity in mouse tumor models and patient-derived colorectal cancer organoids.