Fig. 3: Metabolism reprogramming and ferroptosis in TME.

Ferroptosis is closely related to REDOX metabolism and environmental regulation in the tumor microenvironment, including lipid metabolism, glucose metabolism, amino acid metabolism, acidification stress, hypoxia. Glucose provides the main energy for cell proliferation through aerobic glycolysis. When glucose is absent, ALOX mediates the overexpression of pyruvate dehydrogenase kinase 4 (PDK4), which eventually leads to the occurrence of lipid peroxidation. Mitochondrial glutamate transporter carrier family 25 member 22 (SLC25A22), which regulates GSH expression, can antagonize ferroptosis by promoting stearyl-CoA desaturation enzyme (SCD1) expression to produce MUFA. PUFA, MUFA, and SFA compete in regulating ferroptosis sensitivity. Fatty acids can up-regulate the expression of CD36 in CD8 + T cells and promote the uptake of OX-LDL and OX-PL. This function triggers T-cell ferroptosis, which affects antitumor immunity. In cancer cells, cholesterol antagonizes this process. Cancer cells utilize high levels of anaerobic glycolysis, resulting in the production and release of large amounts of lactate, which leads to extracellular acidification, and elevated lactate levels simultaneously stimulate the AMPK pathway, resulting in increased cell membrane MUFA and antagonize ferroptosis. Hypoxia-regulated transcription of HIF1α up-regulates fatty acid binding proteins 3 and 7 (FABP3/7), which promotes the production of lipid droplets and thus prevents ferroptosis. At the same time, hypoxia promotes WTAP mediated m6A regulation of PPARGC1A/BAMBI/ACSL5 axis and reduces ROS production, thereby down-regulating lipid peroxidation level and ferroptosis. However, HIF 2α promotes the conversion of lipid droplets to fatty acids, leading to the accumulation of PUFA and the occurrence of lipid peroxidation. α-KG α-Ketoglutaric acid, AMPK Adenosine 5‘-monophosphate (AMP)-activated protein kinase, CAF Cancer-Associated Fibroblasts, FABP fatty acid-binding protein, FASN Fatty Acid Synthase, FIN56 Ferroptosis-Inducer-56, GLS2 Glutaminase, GPNA L-γ-Glutamyl-p-nitroanilide hydrochloride, HCAR1 Hydroxycarboxylic Acid Receptor 1, HIF hypoxia-inducible factor, HILPDA Hypoxia Inducible Lipid Droplet Associated, LDH lactate dehydrogenase, LPCAT lyso-phosphatidylcholine acyltransferase, MBOAT membrane bound O-acyl transferase, MCT1 Monocarboxylate transporter 1, MUFA mono-unsaturated fatty acids, OXPHOS oxidative phosphorylation, PDK3 Pyruvate Dehydrogenase Kinase 3, PPARG Peroxisome proliferator-activated receptor gamma, SCD Stearoyl-CoA Desaturase, WTAP Wilms’tumor 1-associating protein.