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Antioxidants
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Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation
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Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: 20 August 2026 | Viewed by 10481

Special Issue Editors

Dr. Antonis Giakountis

E-Mail Website
Guest Editor
Department of Biochemistry & Biotechnology, School of Health Sciences, University of Thessaly, 41335 Larissa, Greece
Interests: lncRNA-mediated transcriptional regulation; RNA–chromatin interactions; chromatin architecture; transcriptional and epigenetic regulation in cancer
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Dimitrios Kouretas

E-Mail Website
Guest Editor
Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece
Interests: antioxidant activity; functional foods; toxicology; redox nutrition; antioxidant administration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Accumulating evidence indicates that the activation or suppression of specific genes leads to an alteration of reactive oxygen species (ROS) levels; this can act as a double-edged sword, mediating tumor suppressive or pro-oncogenic functions, depending on the specific biological context. Thus, a better understanding of the mechanisms that control such genes functions and the most appropriate context of their activation or suppression is a prerequisite for the development of effective therapeutic strategies.

This Special Issue focuses on how ROS levels influence the tumor microenvironment and cancer progression. In this respect, we welcome functional genomics studies that utilize spatial transcriptomics, single-cell sequencing and/or bulk deep sequencing to analyze gene expression changes in tumor-associated stromal cells in response to varying levels of ROS, identifying key signaling pathways, antitumor mechanisms, diagnostic/prognostic biomarkers and potential therapeutic targets for modulating oxidative stress in the tumor microenvironment.

Dr. Antonis Giakountis
Prof. Dr. Dimitrios Kouretas
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • reactive oxygen species
  • tumor microenvironment
  • stroma cells
  • functional genomics
  • spatial transcriptomics
  • single-cell sequencing
  • RNA-seq
  • cancer
  • diagnosis and prognosis
  • biomarkers

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Published Papers (5 papers)

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Editorial

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4 pages, 173 KB  
Editorial
Reactive Oxygen Species and the Lung Cancer Tumor Microenvironment: Emerging Therapeutic Opportunities
by Kostas A. Papavassiliou, Amalia A. Sofianidi and Athanasios G. Papavassiliou
Antioxidants 2025, 14(8), 964; https://doi.org/10.3390/antiox14080964 - 5 Aug 2025
Cited by 1 | Viewed by 1444
Abstract
Lung cancer is the principal cause of cancer-related mortality globally, accounting for the high number of cancer-associated deaths amongst both men and women [...] Full article
(This article belongs to the Special Issue Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation)

Research

Jump to: Editorial, Review

25 pages, 56716 KB  
Article
ITPR1 Maintains Mitochondrial Redox Homeostasis to Drive Glioblastoma Progression Through Recruitment and Activation of DRP1
by Shuyan Luo, Mei Tao, Sihan Li, Xingbo Li, Qian Jiang, Quanji Wang, Zihan Wang, Lv Zhou, Kai Shu, Zhuowei Lei, Yimin Huang and Ting Lei
Antioxidants 2026, 15(5), 550; https://doi.org/10.3390/antiox15050550 - 26 Apr 2026
Viewed by 360
Abstract
Background: Glioblastoma (GBM) exhibits marked cellular heterogeneity and resistance to therapy. Calcium (Ca2+) signaling at endoplasmic reticulum (ER)–mitochondria contact sites has emerged as a key regulator of mitochondrial function and cell fate; however, its lineage-specific role and therapeutic relevance in [...] Read more.
Background: Glioblastoma (GBM) exhibits marked cellular heterogeneity and resistance to therapy. Calcium (Ca2+) signaling at endoplasmic reticulum (ER)–mitochondria contact sites has emerged as a key regulator of mitochondrial function and cell fate; however, its lineage-specific role and therapeutic relevance in GBM remain unclear. Methods: ITPR1 expression was analyzed using single-cell and bulk RNA sequencing (RNA-seq) datasets and validated by immunohistochemistry and survival analyses. Functional studies were conducted using genetic silencing or CRISPR-mediated activation of ITPR1, combined with DRP1 knockdown, Ca2+ imaging, transmission electron microscopy, co-immunoprecipitation, mitochondrial fractionation, and mitochondrial functional assays. Therapeutic efficacy was evaluated in orthotopic GBM xenograft models treated with 2-aminoethoxydiphenyl borate (2-APB), temozolomide (TMZ), or their combination. Results: ITPR1 was enriched in mesenchymal-like malignant cell states and associated with higher tumor grade, recurrence, and poor prognosis. ITPR1 knockdown suppressed GBM cell proliferation and tumor growth while promoting intrinsic apoptosis. Mechanistically, loss of ITPR1 impaired ER-to-mitochondria Ca2+ transfer, disrupted ER–mitochondria contacts, and altered mitochondrial ultrastructure. This was accompanied by reduced DRP1 Ser616 phosphorylation and mitochondrial recruitment, as well as decreased autophagy and mitophagy activity. Consequently, ITPR1 knockdown led to mitochondrial depolarization, increased mitochondrial reactive oxygen species (ROS) accumulation, and activation of mitochondria-dependent apoptosis. Conversely, DRP1 knockdown attenuated the mitochondrial and pro-survival effects induced by ITPR1 overexpression. In vivo, combined treatment with 2-APB and TMZ resulted in greater tumor suppression and prolonged survival compared with either treatment alone, accompanied by increased apoptosis and reduced proliferation in tumor tissues. Conclusions: ITPR1 promotes GBM progression by sustaining ER–mitochondria Ca2+ coupling and DRP1-dependent mitochondrial quality control, thereby maintaining mitochondrial homeostasis and cell survival. Targeting inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling with 2-APB enhances the therapeutic efficacy of TMZ, suggesting that ITPR1-centered Ca2+ signaling may represent a potential therapeutic vulnerability in aggressive GBM. Full article
(This article belongs to the Special Issue Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation)
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18 pages, 4946 KB  
Article
Oxidative Stress by H2O2 as a Potential Inductor in the Switch from Commensal to Pathogen in Oncogenic Bacterium Fusobacterium nucleatum
by Alessandra Scano, Sara Fais, Giuliana Ciappina, Martina Genovese, Barbara Granata, Monica Montopoli, Pierluigi Consolo, Patrizia Carroccio, Paola Muscolino, Alessandro Ottaiano, Alessia Bignucolo, Antonio Picone, Enrica Toscano, Germano Orrù and Massimiliano Berretta
Antioxidants 2025, 14(3), 323; https://doi.org/10.3390/antiox14030323 - 7 Mar 2025
Cited by 7 | Viewed by 2858
Abstract
Background: Fusobacterium nucleatum is a pathobiont that plays a dual role as both a commensal and a pathogen. The oral cavity typically harbors this anaerobic, Gram-negative bacterium. At the same time, it is closely linked to colorectal cancer due to its potential involvement [...] Read more.
Background: Fusobacterium nucleatum is a pathobiont that plays a dual role as both a commensal and a pathogen. The oral cavity typically harbors this anaerobic, Gram-negative bacterium. At the same time, it is closely linked to colorectal cancer due to its potential involvement in tumor progression and resistance to chemotherapy. The mechanism by which it transforms from a commensal to a pathogen remains unknown. For this reason, we investigated the role of oxidative status as an initiatory factor in changing the bacterium’s pathogenicity profile. Methods: A clinical strain of F. nucleatum subsp. animalis biofilm was exposed to different oxidative stress levels through varying subinhibitory amounts of H2O2. Subsequently, we investigated the bacterium’s behavior in vitro by infecting the HT-29 cell line. We evaluated bacterial colonization, volatile sulfur compounds production, and the infected cell’s oxidative status by analyzing HMOX1, pri-miRNA 155, and 146a gene expression. Results: The bacterial colonization rate, dimethyl sulfide production, and pri-miRNA 155 levels all increased when stressed bacteria were used, suggesting a predominant pathogenic function of these strains. Conclusions: The response of F. nucleatum to different oxidative conditions could potentially explain the increase in its pathogenic traits and the existence of environmental factors that may trigger the bacterium’s pathogenicity and virulence. Full article
(This article belongs to the Special Issue Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation)
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Review

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32 pages, 3097 KB  
Review
The Pro-Metastatic Roles of ROS
by Darin E. Gilchrist, Julia A. Ju, Stuart S. Martin and Michele I. Vitolo
Antioxidants 2026, 15(5), 529; https://doi.org/10.3390/antiox15050529 - 22 Apr 2026
Viewed by 258
Abstract
Metastasis is a complex, multistep process in which cancer spreads from its original tumor to other sites in the body. During metastasis, tumor cells move away from the primary tumor and intravasate into the lymphatics or circulation. Surviving tumor cells can then extravasate [...] Read more.
Metastasis is a complex, multistep process in which cancer spreads from its original tumor to other sites in the body. During metastasis, tumor cells move away from the primary tumor and intravasate into the lymphatics or circulation. Surviving tumor cells can then extravasate into and remain in distant tissues until they once again begin to proliferate, forming secondary tumors. An excess of reactive oxygen species (ROS) can promote metastasis, dependent on the ROS molecule, its level of excess, and the examined step within the metastatic cascade. Here, we highlight recent studies where ROS promote epithelial-to-mesenchymal transition, cell migration and invasion, circulating tumor cell survival and disseminated tumor cell dormancy. Additionally discussed are novel in vivo ROS detection methods, FDA-approved therapies and clinical trials that manipulate ROS to improve cancer patient survival. Since metastasis is the major cause of cancer-related death, a better understanding of this process and ROS as a contributing factor will help to identify novel targets for inhibition or prevention. Full article
(This article belongs to the Special Issue Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation)
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25 pages, 1135 KB  
Review
Targeting Redox Signaling Through Exosomal MicroRNA: Insights into Tumor Microenvironment and Precision Oncology
by Moon Nyeo Park, Myoungchan Kim, Soojin Lee, Sojin Kang, Chi-Hoon Ahn, Trina Ekawati Tallei, Woojin Kim and Bonglee Kim
Antioxidants 2025, 14(5), 501; https://doi.org/10.3390/antiox14050501 - 22 Apr 2025
Cited by 19 | Viewed by 4218
Abstract
Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that [...] Read more.
Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8+ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS–miRNA–exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds—such as curcumin, resveratrol, and ginsenosides—which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer. Full article
(This article belongs to the Special Issue Role of Reactive Oxygen Species (ROS) in Tumor Microenvironment Modulation)
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