iProXProteomicsWeijuan GongMus Musculushttp://www.iprox.org/page/project.html?id=IPX0017413000wjgong@yzu.edu.cnYangzhou UniversityiProXfalseForced expression of uncoupling protein 1 (UCP1) counteracts the compromised activity of NK cells by tumor microenvironmentUncoupling protein 1 (UCP1) is a mitochondrial inner membrane protein whose main function is to mediate non-shivering thermogenesis. Dysregulated expression of UCP1 contributes to the pathogenesis of multiple diseases, including cancer. Natural killer (NK) cells, key effectors of antitumor immunity, are substantially impaired in the tumor microenvironment (TME). Here, we showed that UCP1 expression is markedly downregulated in tumor-infiltrating NK (TINK) cells from both colorectal cancer (CRC) patients and tumor-bearing mice and is correlated with impaired effector function. In the TME, TGF-β1 and hypoxia repress the transcription of UCP1 through the downregulation of C/EBPβ. NK cell-specific ablation of UCP1 accelerated tumor growth and reduced the infiltration of TINKs. RNA sequencing revealed an increase in NLRP3 inflammasome-mediated pyroptosis in Ucp1–/– NK cells. UCP1 deficiency synergized with TME stress to increase the uptake of fatty acids and oxidative phosphorylation via the upregulation of CD36/FABP4. This induces mitochondrial damage and excessive release of mitochondrial DNA (mtDNA), triggering the activation of the NLRP3 inflammasome and NK cell pyroptosis. Enforced UCP1 expression in NK cells prevents TME-induced pyroptosis, maintains the antitumor activity in both murine models and patient-derived organoids. Genetically modified expression of UCP1 in NK cells is a potential therapy for patients with tumors.Tue May 26 00:00:00 BST 2026PXD07887610090