CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4

By P. Liao, Weimin Wang, Wen Wang, Ilona Kryczek, Xiong Li, Yingjie Bian, Amanda Sell, Shuang Wei, Sara Grove, Jeffrey K. Johnson and 4 more. Cancer Cell, 2022

770 citations recorded by the source corpus.

SUMMARY Tumor cell intrinsic ferroptosis initiating mechanisms are unknown. Here, we discover 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 ACSL4 pathway is a potential anti-cancer approach.

Subfields: Cancer Research, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/4b86f5ecc590bdca2d7ca5b32a209661a6fd8bd0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Brent R. Stockwell

In Pulmonary and Respiratory Medicine

1. Furong Zeng
2. Yu Meng
3. Yihuang Liu
4. Guangtong Deng
5. Xiang Chen
6. Yuming Sun
7. Jiayuan Le
8. Qian Zhou

Citations in the corpus

• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “330 Mechanistically, IFN γ activates the JAK/STAT1/interferon regulatory factor 1 (IRF1) signaling pathway and promotes IRF1 to bind to the IFN-stimulated response elements in the ACSL4 promoter region, ultimately leading to ACSL4 transcriptional upregulation in cancer cells.”
• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Emerging evidence has demonstrated that CD8 + T cells inhibit tumor cells via induction of necroptosis, pyroptosis, ferroptosis [169, 336, 337], and possibly cuproptosis [338].”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “IFNg also upregulates ACSL4, which aids in the incorporation of PUFAs into PLs (Liao et al., 2022).”