Iron-dependent ferroptosis, a non-apoptotic cell death mechanism, is gaining attention for its role in immune suppression. Ferroptosis, driven by excessive lipid peroxides and iron-dependent reactive oxygen species (ROS), differs from other cell death forms in its immunogenicity. It involves the regulation of the cystine/glutamate transport system xc−, with glutathione (GSH) and glutathione peroxidase 4 (GPX4) preventing toxic lipid peroxide accumulation. Ferroptosis-related factors are implicated in various diseases, including cancer and cardiovascular diseases.
Macrophages, crucial for immune response, are affected by ferroptosis. Erastin and RSL3, ferroptosis inducers, reduce pro-inflammatory cytokines in macrophages. In tumor microenvironments, substances like 8-OHG drive macrophage polarization towards the immunosuppressive M2 type. M1 macrophages, with higher ferritin expression, are more resistant to ferroptosis than M2 macrophages. Pathogen ingestion can also trigger macrophage ferroptosis, releasing harmful lipid peroxides and iron, leading to immunosuppression.
Neutrophils, vital for pathogen defense, are sensitive to ferroptosis. In stroke and systemic lupus erythematosus (SLE), ferroptosis in neutrophils results from reduced PPAR-γ and GPX4 expression, impairing immune function. Aging neutrophils are highly susceptible to ferroptosis, potentially impacting Alzheimer’s disease progression.
T cells, with subsets like Th1, Th2, and Treg, are influenced by ferroptosis. In tumor microenvironments, tumor cells induce T cell ferroptosis via CD36 expression and lipid ROS accumulation, impairing anti-tumor immunity. Tregs, with higher resistance, survive and suppress immune responses. Ferroptosis can also affect T cell subsets differently, with follicular helper T cells being highly sensitive.
B cells, involved in humoral immunity, are impacted by ferroptosis. In lupus nephritis, renal epithelial cell ferroptosis releases factors causing B cell immunosuppression. Different B cell subsets exhibit varying ferroptosis resistance, with B1a cells being highly susceptible.
NK cells, key for tumor surveillance, are impaired by ferroptosis in tumor microenvironments. Tumor cells induce NK cell ferroptosis through PD-L1 binding and PGE2 release, weakening immune responses.
DCs, essential for T cell activation, are affected by ferroptosis. Tumor-associated DCs undergo ferroptosis, reducing their antigen-presenting capacity. In sepsis and atherosclerosis, DC ferroptosis contributes to immunosuppression.
MDSCs, which suppress immune responses, have subtypes with varying ferroptosis resistance. Tumor-associated MDSCs resist ferroptosis, promoting immunosuppression. They compete for cystine, depriving other immune cells and enhancing tumor immune evasion.
Ferroptosis impacts immune responses by reducing immune cell numbers and altering their functions. While some studies suggest it may enhance immunity, the overall effect is immunosuppressive. Understanding ferroptosis resistance in immune cells and their interaction with the microenvironment could offer therapeutic targets for diseases like cancer and infections. Future research should explore the detailed mechanisms of ferroptosis in immune cells to develop effective treatments.
DOI: 10.1007/s11684-024-1080-8