FIGURE 2.

The role of amino acid/glutathione metabolism and lipid metabolism in ferroptosis within the TME. Cystine (Cys2) is transferred into cells by System Xc⁻ at a ratio of 1:1 and then oxidized to cysteine. GPX4 inhibits the toxicity of lipid peroxides through its enzyme activity and maintains the homeostasis of the membrane lipid bilayer. In the process of ferroptosis, PUFAs are prone to peroxidation, resulting in the destruction of the lipid bilayer and affecting membrane function. The free PUFA and CoA are catalyzed by ACSL4 to form derivatives AA-CoA or AdA-CoA, then they are catalyzed by LPCAT3 to form polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). In addition, the immunotreatment-activated CD8⁺ T cells can enhance ferroptosis in cancer cells by releasing IFNγ, which activates the JAK1-STAT1 signaling and thereby inhibit the expression of SLC7A11 and SLC3A2. CAFs could protect cancer cells from chemoresistance-induced oxidative stress by releasing cysteine and GSH to nearby ovarian cancer cells. Meanwhile, CD8⁺ T cells act as a repressor and prevent Cys and GSH release from the CAFs through IFNγ induced SLC7A11 and SLC3A2 downregulation. Cys, cysteine; GPX4, glutathione peroxidase 4; PUFAs, polyunsaturated fatty acids; ACSL4, Acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; IFNγ, interferon γ; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2.