Tumor acidosis promotes disease progression through a stimulation of fatty acid (FA) metabolism in cancer cells. Instead of blocking the use of FAs by acidic cancer cells, we examined whether excess uptake of specific FAs could lead to antitumor effects. We found that n-3 but also remarkably n-6 polyunsaturated FA (PUFA) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding buffering capacity of triglyceride storage into lipid droplets, n-3 and n-6 PUFA peroxidation led to cytotoxic effects in proportion to the number of double bonds and even more so in the presence of diacylglycerol acyltransferase inhibitors (DGATi). Finally, an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers. These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.

肿瘤酸中毒通过刺激癌细胞中的脂肪酸 (FA) 代谢促进疾病进展。我们没有阻止酸性癌细胞对 FA 的使用，而是检查了特定 FA 的过量摄取是否会导致抗肿瘤作用。我们发现在环境酸中毒下，n-3 以及显着的 n-6 多不饱和 FA (PUFA) 选择性地诱导癌细胞中的铁死亡。在超过甘油三酯储存到脂滴中的缓冲能力后，n-3 和 n-6 PUFA 过氧化导致与双键数量成比例的细胞毒性作用，在二酰基甘油酰基转移酶抑制剂 (DGATi) 存在下更是如此。最后，与富含单不饱和脂肪酸的饮食相比，富含 n-3 长链多不饱和脂肪酸的饮食显着延缓了小鼠肿瘤的生长，通过施用 DGATi 或铁死亡诱导剂进一步加重了这种效果。这些数据指出膳食多不饱和脂肪酸是一种选择性辅助抗肿瘤方式，可以有效地补充药理学方法。