Castillo Jesse Garcia, Silveria Stephanie, Schirokauer Leo, Sauquet Antoine, Hung Jessica, Jaworski Grace, Hendricks Joseph M, Sul Hei Sook, Olzmann James A, DuPage Michel
Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Division of Molecular Therapeutics, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Sci Adv. 2026 Jan 23;12(4):eaea3703. doi: 10.1126/sciadv.aea3703.
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) is critically required for regulatory T cell (T 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 in all T cells, or T cells specifically, enhanced tumor control by selectively disrupting T cell immunosuppression within tumors without inciting autoimmune pathology in mice. As opposed to deletion of in all T cells, T cell deletion of 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.
一种新兴的癌症治疗方法是通过药物诱导肿瘤细胞发生铁死亡。然而，破坏更广泛的肿瘤微环境（TME）中的抗铁死亡途径（如在免疫细胞中）的影响仍不明确，可能会使治疗变得复杂。在这里，我们表明，铁死亡抑制蛋白1（FSP1）对于调节性T细胞（Treg）抵抗铁死亡及其在TME中的免疫抑制功能至关重要。与其他典型的铁死亡调节因子（如GPX4和NRF2）相比，只有FSP1在T细胞活化时被诱导。在所有T细胞或特异性T细胞中缺失FSP1，通过选择性破坏肿瘤内T细胞的免疫抑制作用，增强了对肿瘤的控制，而不会在小鼠中引发自身免疫性病理。与在所有T细胞中缺失FSP1不同，在T细胞中特异性缺失FSP1不会损害抗原特异性CD8 + T细胞反应。这些结果揭示了靶向铁死亡调节因子的机会，该调节因子不仅可以直接靶向癌细胞，还可以同时增强抗癌免疫反应而不引发自身免疫。
