Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment

γ, lipopolysaccharide, or GM-CSF] and M2 macrophages (anti-inflammatory phenotype, driven by IL-4, IL-13, or CSF-1), which is determined by the surrounding microenvironmentnHighlight:Early in tumor development, M1-polarized macrophages are potent effector cells that are able to elicit tumor cell disruption.nSticky notes:This is a key paragraphnnHighlight:as tumorigenesis progresses, the TME favors the transition of infiltrated macrophages to the M2 phenotype with protumorigenic activitiesnHighlight:TAMs are widely considered to be M2 macrophages, in that they promote tumor angiogenesis, cancer progression, and immunosuppressionnHighlight:M2-like TAMs inhibit cytotoxic CD8+ T cell antitumor activity and DC maturation by the secretion of transforming growth factor-β (TGF-β) and IL-10nHighlight:inhibitor ligand programmed cell death-ligand 1 (PD-L1) is upregulated, not only in malignant cells but also in TAMs in response to IFN-γ from effector cells [47

], and the interaction of PD-L1 with programmed cell death protein 1 (PD-1) expressed on activated T cells facilitates immune escapenHighlight:TAMs also express PD-1nHighlight:M2-like TAMs deplete amino acids and secrete lactate among the TME, resulting in functional impairment of effector NK and T cellsnHighlight:Iron homeostasis is thus a strictly regulated process that involves uptake, storage, and utilizationnSticky notes:Add effluxnHighlight:iron is a necessary, but potentially toxicnHighlight:divalent metal transporter 1 (DMT1) expressed on duodenum enterocytesnHighlight:Circulating iron predominantly binds to transferrin (TF), forming a complex named TF-bound ironnHighlight:iron exportation is mediated by ferroportin (FPN)nHighlight:transferrin receptor 1 (TFR1)nHighlight:iron is reduced by six-transmembrane epithelial antigen of the prostate 3 (STEAP3) within the endosome and is subsequently released into the cytosol through DMT1 to constitute the cytoplasmic labile iron pool (LIP)nHighlight:fate of this redox-active iron is to be stored in the form of ferritin (FT), utilized for various metabolic needs, or exported out of cells by FPNnHighlight:iron gets oxidized by ceruloplasmin or hephaestin and again combines with TFnHighlight:cellular level is regulated by posttranscriptional mechanisms of iron-responsive element-binding proteins 1 and 2, which interact with iron responsive elements in response to levels of intracellular ironnHighlight:At the systemic level, iron homeostasis is primarily maintained by hepcidin, an important iron regulatory hormonenHighlight:Under high-iron conditions, hepcidin is released by the liver and induces FPN degradation, preventing iron export from duodenum enterocytes, hepatocytes, and macrophages into the blood stream nHighlight:Dysregulated iron homeostasis is considered one of the metabolic hallmarks of malignant cancer cellsnHighlight:These changes contribute to elevated levels of intracellular iron, which is critical in various pathophysiological processes, including cell cycle regulation, DNA synthesis, tumor development, metastasis, and TME modificationnHighlight:Upregulation of TFR1nHighlight:overexpressed DMT1, which is responsible for ferrous iron entry.nHighlight:Ferritin, composing ferritin heavy chains (FTH) and ferritin light chains (FTL), plays a central role in iron storage.nHighlight:high concentrations of plasma FT correlate with a higher tumor stage and poor clinical outcome, suggesting that FT can serve as a prognostic factor in some types of cancer,nHighlight:downregulation of FT accounts for increased chemosensitivity [93 , 94 ], as well as inhibition of tumor growth and developmentnHighlight:only known iron exporter, FPN, and its modulator, hepcidinnHighlight:expression levels of FPN are substantially reduced in prostate and breast cancer compared to those in normal tissues, and they correlate with the degree of tumor aggressivenessnHighlight:Hepcidin can be synthesized in cancer cells, functioning as an autocrine hormone to degrade membrane FPN, increase intracellular concentration, and promote tumor survival, a process jointly controlled by bone morphogenetic protein and IL-6nHighlight:essential role of iron in tumor development is tightly related to its ability to regulate innate and adaptive responses, especially in macrophages and T cellsnHighlight:immune cells compete with tumor cells for iron uptake in the TMEnHighlight:immune cells modify the polarization state to modulate iron metabolism at both local tumor and systemic levelsnHighlight:heme is released and catabolized by heme oxygenase (mainly HO-1) to produce ironnSticky notes:Fe recyclingnHighlight:heme-recycled iron represents the majority of available iron in the body, then stored in FT or delivered to FPNnHighlight:macrophage polarization is associated with changes in iron homeostasisnHighlight:early stages of tumorigenesis, proinflammatory cytokines promote M1-like macrophages (with low levels of FPN and high levels of FT) to display an iron sequestering phenotypenHighlight:early stages of tumorigenesis, proinflammatory cytokines promote M1-like macrophages (with low levels of FPN and high levels of FT) to display an iron sequestering phenotype as an antitumor responsenHighlight:M2-like macrophages exhibit an iron-release phenotype with higher expression of the iron exporter, FPN, and lower expression of the storage protein, FT, thus increasing iron recycling and export into the extracellular space.nHighlight:TAMs have been widely accepted as an anti-inflammatory “iron-donating” phenotype that releases iron to support cancer progressionnHighlight:heme-recycled iron primarily enters the LIP rather than being stored in FT as seen in M1 macrophages, preferentially for the release into the local microenvironmentnSticky notes:M2 like or TAMsnnM1–heme recycle Fe binds to FTnnM2–heme recycle Fe stays in LIP for donationnHighlight:upregulation of FPN, in vitro, TAMs supply tumor cells with iron through the secreted iron-binding protein lipocalin-2 (LCN-2)nHighlight:macrophages are able to secrete FT into the microenvironment to stimulate tumorigenesis, though this proliferative effect is possibly iron-independentnHighlight:deletion of the FTH gene in hematopoietic cells reduces the quantity of T and B cells as a result of an increase in LIP and enlarged ROS formation, suggesting that the iron stored in FT is required for lymphocyte survivalnHighlight:Th1 cells seem more sensitive and more easily susceptible to intracellular iron depletion than Th2 cells nHighlight:T cell function and iron metabolism are intimately relatednHighlight:iron chelatorsn]]>