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]]>

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.


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