Ferroptosis and the Tumor Microenvironment

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2024 Nov 29

PMID 39614322

Authors

Kaisa Cui

Kang Wang

Zhaohui Huang

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is a type of regulated cell death characterized by its non-apoptotic, iron-dependent and oxidative nature. Since its discovery in 2012, extensive research has demonstrated its pivotal roles in tumorigenesis, metastasis and cancer therapy. The tumor microenvironment (TME) is a complex ecosystem comprising cancer cells, non-cancer cells, extracellular matrix, metabolites and cytokines. Recent studies have underscored a new paradigm in which non-cancer cells in the TME, such as immune and stromal cells, also play significant roles in regulating tumor progression and therapeutic resistance typically through complicated crosstalk with cancer cells. Notably, this crosstalk in the TME were partially mediated through ferrotopsis-related mechanisms. This review provides a comprehensive and systematic summary of the current findings concerning the roles of ferroptosis in the TME and how ferroptosis-mediated TME reprogramming impacts cancer therapeutic resistance and progression. Additionally, this review outlines various ferroptosis-related therapeutic strategies aimed at targeting the TME.

Citing Articles

Cell death in tumor microenvironment: an insight for exploiting novel therapeutic approaches.

Wang W, Li T, Wu K Cell Death Discov. 2025; 11(1):93.

PMID: 40064873 PMC: 11894105. DOI: 10.1038/s41420-025-02376-1.

Ferroptosis in Pulmonary Disease and Lung Cancer: Molecular Mechanisms, Crosstalk Regulation, and Therapeutic Strategies.

Guo D, Cai S, Deng L, Xu W, Fu S, Lin Y MedComm (2020). 2025; 6(3):e70116.

PMID: 39991627 PMC: 11847630. DOI: 10.1002/mco2.70116.

References

Asao T, Tobias G, Lucotti S, Jones D, Matei I, Lyden D . Extracellular vesicles and particles as mediators of long-range communication in cancer: connecting biological function to clinical applications. Extracell Vesicles Circ Nucl Acids. 2024; 4(3):461-485. PMC: 11067132. DOI: 10.20517/evcna.2023.37. View

Cheu J, Lee D, Li Q, Goh C, Bao M, Yuen V . Ferroptosis Suppressor Protein 1 Inhibition Promotes Tumor Ferroptosis and Anti-tumor Immune Responses in Liver Cancer. Cell Mol Gastroenterol Hepatol. 2023; 16(1):133-159. PMC: 10230009. DOI: 10.1016/j.jcmgh.2023.03.001. View

Schwantes A, Wickert A, Becker S, Baer P, Weigert A, Brune B . Tumor associated macrophages transfer ceruloplasmin mRNA to fibrosarcoma cells and protect them from ferroptosis. Redox Biol. 2024; 71:103093. PMC: 10900931. DOI: 10.1016/j.redox.2024.103093. View

Viswanadhapalli S, Luo Y, Sareddy G, Santhamma B, Zhou M, Li M . EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer. Mol Cancer Ther. 2019; 18(8):1341-1354. PMC: 6677593. DOI: 10.1158/1535-7163.MCT-18-1258. View

Li L, Peng X, Yu T, Xu H, Han N, Yang X . Dihydroartemisinin remodels macrophage into an M1 phenotype ferroptosis-mediated DNA damage. Front Pharmacol. 2022; 13:949835. PMC: 9403990. DOI: 10.3389/fphar.2022.949835. View

Kim R, Hashimoto A, Markosyan N, Tyurin V, Tyurina Y, Kar G . Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature. 2022; 612(7939):338-346. PMC: 9875862. DOI: 10.1038/s41586-022-05443-0. View

Li H, Yang C, Wei Y, Li X, Jiang W, Xu Y . Ferritin light chain promotes the reprogramming of glioma immune microenvironment and facilitates glioma progression. Theranostics. 2023; 13(11):3794-3813. PMC: 10334844. DOI: 10.7150/thno.82975. View

Foster D, Januszyk M, Delitto D, Yost K, Griffin M, Guo J . Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer Cell. 2022; 40(11):1392-1406.e7. PMC: 9669239. DOI: 10.1016/j.ccell.2022.09.015. View

Abe C, Miyazawa T, Miyazawa T . Current Use of Fenton Reaction in Drugs and Food. Molecules. 2022; 27(17). PMC: 9457891. DOI: 10.3390/molecules27175451. View

10.

Galluzzi L, Bravo-San Pedro J, Vitale I, Aaronson S, Abrams J, Adam D . Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2014; 22(1):58-73. PMC: 4262782. DOI: 10.1038/cdd.2014.137. View

11.

Wang D, Li X, Jiao D, Cai Y, Qian L, Shen Y . LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia. J Hematol Oncol. 2023; 16(1):30. PMC: 10044814. DOI: 10.1186/s13045-023-01429-1. View

12.

Li J, Liu J, Zhou Z, Wu R, Chen X, Yu C . Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci Transl Med. 2023; 15(720):eadg3049. DOI: 10.1126/scitranslmed.adg3049. View

13.

Elhanani O, Ben-Uri R, Keren L . Spatial profiling technologies illuminate the tumor microenvironment. Cancer Cell. 2023; 41(3):404-420. DOI: 10.1016/j.ccell.2023.01.010. View

14.

Jiang F, Jia K, Chen Y, Ji C, Chong X, Li Z . ANO1-Mediated Inhibition of Cancer Ferroptosis Confers Immunotherapeutic Resistance through Recruiting Cancer-Associated Fibroblasts. Adv Sci (Weinh). 2023; 10(24):e2300881. PMC: 10460848. DOI: 10.1002/advs.202300881. View

15.

Gong L, Tian L, Cui K, Chen Y, Liu B, Li D . An off-the-shelf small extracellular vesicle nanomedicine for tumor targeting therapy. J Control Release. 2023; 364:672-686. DOI: 10.1016/j.jconrel.2023.11.013. View

16.

Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D . CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020; 19(1):43. PMC: 7045485. DOI: 10.1186/s12943-020-01168-8. View

17.

Li H, Yang P, Wang J, Zhang J, Ma Q, Jiang Y . HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. J Hematol Oncol. 2022; 15(1):2. PMC: 8740349. DOI: 10.1186/s13045-021-01223-x. View

18.

Li C, Phoon Y, Karlinsey K, Tian Y, Thapaliya S, Thongkum A . A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients. J Exp Med. 2021; 219(1). PMC: 8611729. DOI: 10.1084/jem.20202084. View

19.

Feng Q, Fang W, Guo Y, Hu P, Shi J . Nebulized Therapy of Early Orthotopic Lung Cancer by Iron-Based Nanoparticles: Macrophage-Regulated Ferroptosis of Cancer Stem Cells. J Am Chem Soc. 2023; 145(44):24153-24165. DOI: 10.1021/jacs.3c08032. View

20.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View