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2026

Nature . 2026 May;653(8113):200-211. doi: 10.1038/s41586-026-10193-4. Epub 2026 Mar 4.

Lipid metabolism drives dietary effects on T cell ferroptosis and immunity

Naiqi Wang, Zhian Chen, Yin Yao, Chenglong Sun, Wei Wei, Lei Sun, Hao Zhang, Feng Li, Daniel Butcher, Shi-Ran Sun, Jialei Gong, Yingxin Celia Jiang, Yanfei Qi, Jingxuan Huang, Sam Nettelfield, Rui Liu, Xiaoyue Zheng, Chenyu Li, Yang Fu, Haoyuan Geng, Limin Zhao, Hongjian Sun, Yang Yang, Yexin Ge, Mehrdad Pazhouhandeh, Christopher K. Barlow, Katherine Joanna Jeppe, Joseph Yunis, Chen Zhu, Yunbo Wei, Xiaowen Liang, Kim Bridle, David M. Frazer, Siok-Keen Tey, Yuhua Li, Zhaohui Yang, Minglei Shu, Zheng Liu, Darrell Crawford & Di Yu

Frazer Institute, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, Queensland, Australia. Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China. Hubei Engineering Research Center for Precision Medicine in Chronic Nasal Diseases, Wuhan, China. Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. Key Laboratory for Natural Active Pharmaceutical Constituents Research in Universities of Shandong Province, School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China. School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China. Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong, China. Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Minda Hospital of Hubei Minzu University, Enshi, China. Hubei Provincial Clinical Medical Research Center for Nephropathy, Minda Hospital of Hubei Minzu University, Enshi, China. Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia. Ian Frazer for Children's Immunotherapy Research, Children's Health Research Centre, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, Queensland, Australia. Monash Proteomics and Metabolomics Platform, Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, Queensland, Australia. Faculty of Health, Medicine and Behaviour Sciences, University of Queensland, Brisbane, Queensland, Australia. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Shandong Artificial Intelligence Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China. Frazer Institute, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, Queensland, Australia.

Service type: Stock strains

Abstract

Ferroptosis, a major mechanism of non-apoptotic programmed cell death, critically regulates the homeostasis and functionality of peripheral CD4+ and CD8+ T cells1-6. Here we demonstrate that in mouse, resistance of T cells to ferroptosis depends critically on the composition of standard rodent diets, and that dietary effects on ferroptosis (DEFs) have a crucial role in regulation of T cell homeostasis and immune responses. DEFs are microbiota-independent and are driven by variations in dietary polyunsaturated and monounsaturated fatty acids (PUFAs and MUFAs) that lead to variations in abundance of lipid species in lymphoid tissues and T cells. Consistently, ferroptosis resistance of human T cells also correlated with plasma lipid profiles across multiple healthy cohorts, exhibiting negative associations with PUFA/MUFA ratios in major lipid classes. DEFs dictate T cell resilience in the absence of the essential lipid peroxide scavenger GPX4 and broadly modulate T cell-dependent humoral immunity and T cell-mediated anti-tumour immunity, including in chimeric antigen receptor T cell therapy. Mechanistically, ACSL4, which preferentially biosynthezises PUFA-containing phospholipids7, is highly expressed in T cells and underpins DEF-mediated regulation of follicular helper T (TFH) cell generation and function. Our findings reveal the physiological significance of lipid metabolism in driving DEFs in immunity and suggest strategies targeting lipid metabolism to enhance vaccine efficacy and T cell-mediated immunotherapy.