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, suppresses 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

SUBMITTER: Lang X 

PROVIDER: S-EPMC6891128 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature