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

A burgeoning approach to treating cancer is the pharmacological induction of ferroptotic cell death of tumor cells. However, the impact of disrupting antiferroptotic 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 (T_reg cell) resistance to ferroptosis and their immunosuppressive function within the TME. Compared to other canonical ferroptosis regulators such as GPX4 and NRF2, only FSP1 was induced upon T cell activation. Deletion of <i>Aifm2</i> in all T cells, or T_reg cells specifically, enhanced tumor control by selectively disrupting T_reg cell 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 an opportunity for targeting a regulator of ferroptosis that can not only directly target cancer cells but also simultaneously enhance anticancer immune responses without inciting autoimmunity.