Fig. 2: Effects of immune cells on ferroptosis in TME.

T cells in TME release IFN-γ which down-regulate system xc^- to promote ferroptosis of cancer cells by GSH depletion. IFN-γ also promotes the differentiation of macrophages into M1 type, acquiring the ability to kill and phagocytoze cells, and inhibiting the development of tumors. DC is an important role in the occurrence of ferroptosis. Iron-tropic regulators further affect the activation of T cells by hindering the antigen presentation function of DC cells and hinder the occurrence of ferroptosis. CAFs are the main force of tumor resistance to ferroptosis, which can provide a large amount of GSH and Cys for tumors. However, IFN-γ secreted by T cells breaks down GSH by binding to CAF to generate GGT5, reducing tumor absorption. In the absence of GPX4, although the ferroptosis level of the tumor itself is increased, it also leads to the ferroptosis of Treg itself, leading to its loss of anti-tumor ability. On the other hand, it also leads to spontaneous ferroptosis of PMN-MDSCs and subsequent release of factors that inhibit the anti-tumor effects of T cells and TAMs. Thus, immune cells in the TME interact and work together to regulate ferroptosis. 8-OHG 8-hydroxyguanosine, CAF Cancer-Associated Fibroblasts, DC dentric cell, ER Endoplasmic reticulum, ESCRT endosomal sorting complexes required for transport, GGT γ-Glutamyl Transferase, HMGB1 High mobility group box 1 protein, JAK Janus Kinase, KRAS Kirsten rats arcomaviral oncogene homolog, MDSC Myeloid-derived suppressor cells, MPO myeloperoxidase, MZB Marginal Zone B And B1 Cell Specific Protein, NET Neutrophil Extracellular Traps, PADI4 Peptidyl Arginine Deiminase 4, PGE2 prostaglandin E2, PMN polymorphonuclear, PPARG peroxisome proliferator-activated receptor gamma, RSL3 RAS-selective lethal 3, STAT signal transducer and activator of transcription, STING stimulator of interferon genes, TAM tumor-associated macrophage, XBP1 X-box binding protein 1.