Selective disruption of lipid peroxide homeostasis in intratumoral regulatory T cells by targeting FSP1 enhances cancer immunity

A burgeoning approach to treat cancer is the pharmacological induction of ferroptotic cell death of tumor cells. However, the impact of disrupting anti-ferroptotic pathways in the broader tumor microenvironment (TME), such as in immune cells, is still undefined and may complicate treatments. Here, we show that Ferroptosis Suppressor Protein 1 (FSP1<i>/Aifm2</i>) is critically required for regulatory T cell (Treg) resistance to ferroptosis and their immunosuppressive function within the TME. Compared to other canonical ferroptosis regulators such as GPX4, GCH1, and NRF2, only FSP1 was induced upon T cell activation. Deletion of <i>Aifm2</i> in all T cells, or Tregs specifically, enhanced tumor control by selectively disrupting Treg immunosuppression within tumors without inciting autoimmune pathology in mice. As opposed to deletion of <i>Gpx4</i> in all T cells, T cell deletion of <i>Aifm2</i> did not impair antigen-specific CD8⁺ T cell responses. These results reveal a unique opportunity for targeting a regulator of ferroptosis that can not only directly target cancer cells, but also simultaneously enhance anti-cancer immune responses without inciting autoimmunity.