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CD8 + T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4.
- Source :
-
Cancer cell [Cancer Cell] 2022 Apr 11; Vol. 40 (4), pp. 365-378.e6. Date of Electronic Publication: 2022 Feb 24. - Publication Year :
- 2022
-
Abstract
- 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 <superscript>+</superscript> 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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2022 Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 40
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 35216678
- Full Text :
- https://doi.org/10.1016/j.ccell.2022.02.003