Fig. 1: Ferroptosis with EMT and immune cells in the TME.
From: Emerging roles of ferroptosis-related miRNAs in tumor metastasis
A Some EMT-TFS can induce the expression of DDR2 to increase the ferroptosis sensitivity of cancer cells after EMT through the Hippo pathway, and inhibit the expression of iron export proteins to maintain intracellular iron overload and higher levels of ROS. The α6β4 integrin located on the cell membrane can activate the Src and STAT3 pathways to inhibit the expression of the long polyunsaturated fatty acid-rich enzyme ACSL4. The adhesion protein PVRL4 inhibits ferroptosis through the PVRL4/α6β4/Src signaling pathway. CEMIP interacts with inositol 1/4 to activate NRF2 to increase SLC7A11 transcription, and cancer cells uptake cystine to increase ferroptosis resistance after ECM detachment. B Iron overload can increase intracellular ROS, and activate macrophages to M1 phenotype by enhancing P300 /CBP acetyltransferase activity and promoting p53 acetylation, thereby promoting the progression of inflammation. At the same time, RRM2 gene expression can inhibit ferroptosis, promote the polarization of M2 macrophages, and inhibit the polarization of M1 macrophages to promote cancer progression and metastasis. The increased expression of NOX4 can activate the PI3K/Akt signaling pathway through the increase of ROS, causing the increased secretion of various cytokines such as VEGF-C, IL-8, and CCL7, and promoting the polarization of M2 phenotype macrophages. In cancer cells, M1 macrophages can activate CD8 + T cells to cause ferroptosis and play a killing role. CD8 + T cells downregulate the expression of SLC3A2 and SLC7A11, two subunits of XC—by releasing INFγ, which affects the uptake of cystine and promotes the production of ROS and ferroptosis. INFγ could also activate ACSL4 expression through the STAT1-IRF1 signaling pathway and trigger ACSL4-dependent ferroptosis. Cholesterol can increase the expression of CD36 in CD8 + T cells, increase the uptake of fatty acids by T cells, induce lipid peroxidation and ferroptosis of CD8 + T cells, and cause tumor-killing ability dysfunction.
