CD8⁺ T Cell-Induced Ferr optosis via a Positive Feedback Mechanism to Overcome Immune Resistance

Abstract

This research elucidates a novel strategy wherein CD8⁺ T cells overcome tumor immune evasion by initiating ferroptosis and establishing a self-sustaining positive feedback loop. Unlike traditional cytolytic pathways employed by CD8⁺ T cells (e.g., Fas-L/Fas and perforin/ granzyme mechanisms), the interferon-gamma (IFN- γ)-facilitated ferroptosis pathway unveils a distinct immunoregulatory role. Ferroptosis is an iron-dependent, non-apoptotic form of cell death driven by excessive lipid peroxidation, loss of mitochondrial membrane integrity, and eventual plasma membrane disruption. Crucially, beyond direct tumor cell killing, the process leads to emission of damage-associated molecular patterns (DAMPs), which potently stimulate dendritic cell maturation and enhance antigen-specific T cell responses. This establishes a cyclic “immune activation--ferroptosis- -immune reactivation” cascade, effectively alleviating immunosuppression within the tumor microenvironment (TME). Our comprehensive analysis demonstrates that CD8⁺ T cell-secreted IFN-γ downregulates SLC7A11, limiting cystine uptake and impairing glutathione (GSH) biosynthesis, thereby inactivating GPX4. Concurrently, IFN-γ upregulates ACSL4, promoting esterification of polyunsaturated fatty acids (PUFAs) into phospholipids and increasing susceptibility to lipid peroxidation. Together, these synergistic changes induce robust ferroptosis. This mechanism offers a transformative therapeutic perspective for tackling resistance to immune checkpoint inhibitors, with considerable theoretical and clinical implications for next-generation cancer immunotherapies.