癌症研究
棕榈油酸
生物
免疫系统
花生四烯酸
免疫
CD8型
细胞
化学
脂肪酸
免疫学
生物化学
棕榈酸
酶
作者
Peng Liao,Weichao Wang,Ilona Kryczek,Li Xiong,Yingjie Bian,Amanda Sell,Shuang Wei,Sara Grove,Jeffrey Johnson,Paul D. Kennedy,Miguel A. Gijón,Yatrik M. Shah,Weiping Zou
出处
期刊:Cancer Cell
[Elsevier]
日期:2022-04-01
卷期号:40 (4): 365-378.e6
被引量:273
标识
DOI:10.1016/j.ccell.2022.02.003
摘要
Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8+ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.
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