ArticleJournal of translational medicine2021
Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages.
Article in Journal of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 51 citations in OpenAlex.
- scRNA-seq and bulk RNA-seq reveal the characteristics of macrophage copper metabolism and establish a risk signature in hepatocellular carcinoma.Translational cancer research · 2026Article
- Immune network remodeling driven by ferroptosis: Bidirectional interaction mechanisms among multiple immune cells in the lung cancer immune microenvironment (Review).Oncology reports · 2026Review
- Transferrin receptor 1: an emerging therapeutic target in cancer beyond iron metabolism.Cancer cell international · 2026Review
- Mechanistic Research on the Crosstalk Between Macrophage Polarization and Energy Metabolic Reprogramming in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2026Review
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- Iron homeostasis and macrophage polarization in oral squamous cell carcinoma: mechanisms and therapeutic perspectives.Frontiers in immunology · 2026Review
- Metal Ions Within the Neuro-Immune-Tumor Axis.Journal of immunology research · 2026Review
- CD71 as an independent prognostic factor in pediatric B-ALL: a regional multicenter retrospective study in Southern China (SCCLG-ALL-2016).Therapeutic advances in medical oncology · 2026Article
- Metal homeostasis as a therapeutic lever: advancing metalloimmunology to remodel the tumor microenvironment and enhance cancer immunotherapy.Theranostics · 2026Review
- Cross-scale modeling reveals a TFRC-driven immunosuppressive macrophage niche in cervical cancer.Frontiers in immunology · 2026Article
- Advances in ferroptosis mechanisms and therapeutic potential in head and neck squamous cell carcinoma.Frontiers in cell and developmental biology · 2026Review
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- Lung cancer cell derived sEVs enhance the metastasis of non-small cell lung cancer via SNHG12/miR-326/SLC7A11 axis.Cancer biology & therapy · 2025Article
- Advances in Tumor-Derived Exosomal Non-Coding RNAs Regulating M2 Macrophage Polarization: Molecular Mechanisms and Signaling Pathway.Cancer medicine · 2025Review
- Beyond Iron: The Roles of CD71 in the Pathophysiology of Cancer-A Comprehensive Review.Journal of clinical medicine · 2025Review
- Immunometabolic reprogramming in lung cancer: interplay between immune and stem-like cells in immune checkpoint inhibitor resistance.Journal of translational medicine · 2025Review
- Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance.Cell death discovery · 2025Review
- Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2025Review
- A ferritin-targeted biohybrid triggering ferroptosis immunotherapy via activating endogenous iron and replenishing exogenous iron simultaneously.Nature communications · 2025Article
- Silencing PTPN2 with nanoparticle-delivered small interfering RNA remodels tumor microenvironment to sensitize immunotherapy in hepatocellular carcinoma.Acta pharmaceutica Sinica. B · 2025Article
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundTumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM.
methodsTAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages.
resultsWe revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages.
conclusionsCollectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.
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