Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11

By Xueting Lang, Michael D. Green, Wen Wang, Jiali Yu, J. E. Choi, Long Jiang, P. Liao, Jiajia Zhou, Qiang Zhang, Ania Dow and 13 more. Cancer Discovery, 2019

837 citations recorded by the source corpus.

A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc−, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/4cf4d4c75ad9cc74edef20e45380e27ac5d878d9

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In Molecular Biology

1. D. Tang
2. R. Kang
3. Guido Kroemer
4. Xin Chen
5. W. Zou
6. P. Lei
7. Pranavi Koppula
8. B. Gan

In Oncology

1. Guido Kroemer
2. D. Tang
3. W. Zou
4. R. Kang
5. Xin Chen
6. Lieping Chen

In Pulmonary and Respiratory Medicine

1. D. Tang
2. Guido Kroemer
3. R. Kang
4. Xin Chen
5. Brent R. Stockwell
6. P. Lei
7. B. Gan
8. Furong Zeng

Citations in the corpus

• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Mechanistically, radiation causes lipid peroxidation and ferroptotic cell death through three parallel mechanisms at least [198, 319, 320].”
• CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 (2022, background): “The combination of a synthetic ferroptosis inducer and PD-L1 blockade synergistically enhances the anti-tumor efficacy in preclinical models (Lang et al., 2019; Wang et al., 2019).”
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “327,387 The mechanisms through which radiotherapy induces ferroptosis are multifa-ceted.”
• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “system leading to reduced cyst(e)ine uptake which enhances tumor lipid oxidation and induce ferroptosis.(28) This acts synergistically with interferons released by immunotherapy-activated CD8+ T cells, further demonstrating the robust antitumor effects of immunotherapy combined with radiotherapy.”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, neutral): “, 2020) alone or in combination with immunotherapy (Lang et al., 2019).”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “It will be important to evaluate the likely complex relationship between STING1 activation, autophagy status, and ferroptotic effects during radiotherapy (Lang et al., 2019; Liu et al., 2020a; Yamazaki et al., 2020).”
• Ferroptosis: mechanisms and links with diseases (2021, background): “The expression of the Ataxia-Telangiectasia mutated gene in irradiated tumor cells would inhibit the expression of SLC7A11, blocking cystine uptake and resulting in lipid peroxidation accumulation.(194) Ionizing radiation also upregulates the expression of ACSL4 in human cancer cells.”