Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11

Abstract

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.

Upregulation of Bag3 Exacerbates Cervical Cancer Progression by Impairing Immune Response and Inhibiting Cell Ferroptosis

“…Additionally, IFN-gamma derived from CD8+ T cells can enhance tumor lipid oxidation and ferroptosis [32]. In our current work, we observed that loss of Bag3 ameliorated the development of cervical cancer by inducing immune responses and ferroptosis.…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…Later was discovered that CD8 + T cells activate tumor ferroptosis during treatment with anti-CTLA4 and anti-PD-L1 immunotherapies (238). Furthermore, both immunotherapy and radiotherapy independently initiate ferroptosis, yet when combined act synergistically sensitizing tumors and improving tumor control (239). The mechanism was attributed to the release of IFNγ from CD8 + T cells which impaired tumor cell uptake of cysteine by system Xc − and resulted in iron-dependent lipid peroxidation and ferroptosis.…”

Aberrant SLC6A14 Expression Promotes Proliferation and Metastasis of Colorectal Cancer Via Enhancing the JAK2/STAT3 Pathway

“…In some subtypes of human breast cancer, high expression of SLC7A5 was strongly associated with higher grade, larger tumor volume, which may serve as a promising therapeutic target [31]. Another transporter has attracted increasing attention regarding tumor growth is SLC7A11, which protected tumor cells against ferroptosis-mediated cell death when suffered from oxidative stress and nitrosative stress [32].…”