CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.
Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.
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树突状细胞（DCs）协调针对病原体和肿瘤的适应性免疫应答，然而膳食脂质如何影响DC代谢和功能在很大程度上仍未得到探索。在此，我们表明膳食多不饱和脂肪酸（PUFAs）通过核因子E2相关因子2（Nrf2）依赖性调控铁死亡来决定DC活性。在小鼠中，富含n-6 PUFA的饮食抑制了DC的Nrf2信号传导，耗竭了谷胱甘肽，并诱导了脂质过氧化和铁死亡，从而损害了抗原呈递。相比之下，膳食n-3 PUFAs增强了Nrf2信号传导和氧化还原稳态，保护了DC完整性和T细胞致敏。药理学Nrf2激活或铁死亡抑制恢复了来自n-6 PUFA喂养小鼠的DCs功能。
值得注意的是，用富含n-3 PUFAs（而非n-6 PUFAs）饮食驯化的DCs进行过继免疫治疗，引发了持久的、T细胞依赖性的转移性卵巢癌控制。这些发现将膳食PUFAs确定为DCs中Nrf2-谷胱甘肽-铁死亡轴的关键调节因子，并揭示了一个可用于改善癌症免疫治疗的氧化还原敏感性代谢检查点。
Dendritic cells (DCs) orchestrate adaptive immune responses to pathogens and tumors, yet how dietary lipids influence DC metabolism and function remains largely unexplored.
Here we show that dietary polyunsaturated fatty acids (PUFAs) govern DC activity via Nuclear factor erythroid 2-like 2 (Nrf2)-dependent control of ferroptosis. In mice, an n-6 PUFA-enriched diet suppressed DC Nrf2 signaling, depleted glutathione, and induced lipid peroxidation and ferroptosis, thereby compromising antigen presentation.
By contrast, dietary n-3 PUFAs enhanced Nrf2 signaling and redox homeostasis, preserving DC integrity and T cell priming. Pharmacologic Nrf2 activation or ferroptosis inhibition restored the function of DCs from n-6 PUFA-fed mice.
Notably, adoptive immunotherapy with DCs conditioned by a diet rich in n-3 PUFAs-but not n-6 PUFAs-elicited durable, T cell-dependent control of metastatic ovarian cancer.
These findings identify dietary PUFAs as key modulators of the Nrf2-glutathione-ferroptosis axis in DCs and reveal a redox-sensitive metabolic checkpoint that can be leveraged to improve cancer immunotherapy.
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