Steering tumors towards a ferroptosis-mediated immunogenic death by exploiting vulnerabilities in lipid metabolism

While precision therapies are revolutionizing the way in which we treat cancer, a growing body of evidence indicates that the long-term success of current treatments heavily relies on the induction of efficient cell death, along with the elicitation of tumor antigen-directed antitumor immunity. Among the key factors determining this response is the mechanism of cell death induced by therapeutic interventions. Whereas classical apoptosis often causes immune stealth, other more recently discovered forms of regulated cell death appear to be more immunogenic. One of these recently described forms of cell death is ferroptosis, an iron-dependent cell death modality that relies on the propagation of peroxidation of polyunsaturated fatty acids. In view of the mounting evidence that oxidized lipids function as key mediators of immune responses both in cancer and in inflammatory disease and based on our recent findings that pharmacological as well as dietary intervention can evoke a marked shift towards polyunsaturation of lipids in tumors, we propose a novel treatment concept in which vulnerabilities in lipid metabolism are exploited to sensitize cancer cells to ferroptosis and to enhance the anti-tumor immunity, leading to a more complete and sustained tumor eradication.