Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis

Abstract

The current challenge in oncology is to rationally and effectively integrate immunotherapy with traditional treatment modalities including radiotherapy. Multiple preclinical studies have suggested radiotherapy may elicit abscopal responses. There is limited understanding if radiotherapy and immunotherapy synergize to promote control of irradiated tumors. We have recently shown that radiotherapy and immunotherapy induce ferroptosis, a novel form of programmed cell death in which excessive cell membrane oxidation results in cell death. We hypothesized that ferroptosis may be a novel point of synergy between radiotherapy and immunotherapy within irradiated tumors. We use in vivo lipid oxidation quantification, pharmacologic perturbation, Crispr knockout, clonogenic survival, in vivo tumor growth, and flow cytometry to understand the importance of lipid oxidation to radiotherapy and immunotherapy efficacy. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in multiple human and murine preclinical models in vitro and in vivo. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, interferon gamma 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 enhanced ferroptosis. Tumoral ferroptosis correlates with tumor control in preclinical models. Ferroptosis is a novel and previously unappreciated mechanism of radiotherapy and immunotherapy efficacy. Examining the induction of programmed cell death can promote the rational development of effective combinatorial cancer therapy.