Ferroptosis promotes immune suppression in tumors

Ferroptosis is a form of non-apoptotic cell death that relies on iron and has recently attracted interest for its influence on immune suppression. This process is marked by the accumulation of harmful lipid peroxides and reactive oxygen species. Ferroptosis differs from other types of cell death because it has distinct effects on the immune system. Macrophages play a key role in the immune response and are significantly impacted by ferroptosis. Inducers like Erastin and RSL3 diminish the production of pro-inflammatory cytokines in these cells. In cancer, substances can push macrophages towards an M2 type that suppresses the immune response. M1 macrophages, which have more ferritin, are more resilient to ferroptosis than M2 macrophages. Additionally, macrophages can undergo ferroptosis after ingesting pathogens, leading to the release of toxic materials that suppress immunity. Neutrophils, important for fighting infections, are also vulnerable to ferroptosis. This process is linked to conditions like stroke and lupus, where a decrease in certain protective proteins reduces their immune function. Older neutrophils show high sensitivity to ferroptosis, possibly influencing diseases such as Alzheimer's. Ferroptosis affects T cells in various ways. In tumor environments, cancer cells can trigger T cell ferroptosis, weakening their ability to fight tumors. Regulatory T cells (Tregs) are more resistant to ferroptosis, which helps them suppress other immune responses. Different T cell types respond differently to ferroptosis, with some being more susceptible than others. B cells, which help produce antibodies, are also affected by ferroptosis. In certain conditions like lupus nephritis, dying cells can release factors that suppress B cell function. The resistance to ferroptosis varies among B cell types, impacting their roles in the immune response. Natural killer (NK) cells, important for monitoring tumors, can be weakened by ferroptosis. In tumors, signals from cancer cells can induce ferroptosis in NK cells, undermining their effectiveness. Dendritic cells (DCs), crucial for activating T cells, also suffer from ferroptosis. This process affects their ability to present antigens. Myeloid-derived suppressor cells (MDSCs), which help dampen immune responses, show varied resistance to ferroptosis. Those associated with tumors tend to resist it, enhancing their immunosuppressive effects while limiting other immune cells’ activities. In summary, ferroptosis affects the immune response by reducing the number and functionality of immune cells. Although some studies indicate it might bolster immunity, the dominant effect appears to be immunosuppressive. Understanding how different immune cells resist ferroptosis could lead to new therapies for cancer and infections. Future research is needed to uncover the specific mechanisms behind ferroptosis in immune cells.