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Cancers
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Radiosensitivity and Radiotoxicity in Cancer
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Radiosensitivity and Radiotoxicity in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (31 July 2026) | Viewed by 5573

Editor

Prof. Dr. Alexandros Georgakilas

E-Mail Website
Guest Editor
DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou Campus, 15780 Athens, Greece
Interests: radiation biology; cancer biology; DNA damage and repair; oxidative stress; carcinogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Radiation therapy is considered the primary modality in cancer treatment. Technological improvements have optimized radiation therapy systems toward more precise dose delivery in the tumor area while at the same time minimizing unwanted doses to normal tissues.

Two of the most critical parameters for the successful outcome for any tumor treatment are radiosensitivity of the tumor and the radiotoxicity of normal tissues, leading to a range of adverse effects in patients in the short and long terms. With this Special Issue, we aim to identify and shed light to the pathways and mechanisms leading to improved tumor treatment using different types of radiation, from X-rays, electrons, to protons and carbons. Advancements in radiation therapy systems are also of great interest. Therefore, groups working on different aspects of radiation therapy, from accelerators to clinical outcomes, combinations with immunotherapy, FLASH, or other modalities, are welcome to submit their research or review work. Preclinical and clinical trials are also welcome to be included. Although the primary emphasis will be on human patients, other non-human patient studies are also welcome to be submitted. Groups working on genetic factors and biomarkers are encouraged to consider this Special Issue. Last but not least, based on the development of important roles of bioinformatics and systems biology, studies using specific tools for the delineation of molecular pathways improving tumor control and/or reducing toxicity are invited to be submitted. 

Prof. Dr. Alexandros Georgakilas
Guest Editor

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 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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly 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

  • radiation therapy
  • clinical outcome
  • radiosensitivity
  • radiotoxicity
  • biomarkers
  • bioinformatics
  • systems biology

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Published Papers (4 papers)

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Research

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30 pages, 58453 KB  
Article
Time- and Dose-Dependent Effects of Irradiation on Endothelial and Tumor Endothelial Cells: Transcriptional, Molecular, and Functional Changes Driving Activation In Vitro and In Vivo
by Iva Santek, Gregor Sersa and Bostjan Markelc
Cancers 2025, 17(17), 2842; https://doi.org/10.3390/cancers17172842 - 29 Aug 2025
Cited by 1 | Viewed by 2336
Abstract
Background: Irradiation (IR) targets cancer cells, but also the tumor microenvironment, including the tumor’s blood vessels. In addition to tumor endothelial cell (TEC) apoptosis, IR can lead to TEC activation, potentially increasing immune cell infiltration. However, the changes underlying the IR-induced activation of [...] Read more.
Background: Irradiation (IR) targets cancer cells, but also the tumor microenvironment, including the tumor’s blood vessels. In addition to tumor endothelial cell (TEC) apoptosis, IR can lead to TEC activation, potentially increasing immune cell infiltration. However, the changes underlying the IR-induced activation of endothelial cells (ECs) are poorly understood. This study investigated dose- and time-dependent molecular and functional responses of murine and human EC lines to IR in vitro and TECs in vivo in murine tumor models of colorectal carcinoma. Methods: HUVEC, EA.hy926, and Hulec5a, as well as murine bEND.3, 2H11, and SVEC4-10 EC lines, were irradiated with single doses of 2–10 Gy. EC proliferation and survival after IR were assessed by staining all nuclei (Hoechst 33342) and dead cells (propidium iodide) every 24 h for 5 days using the Cytation 1 Cell Imaging Multi-Mode Reader. RNA sequencing analysis of HUVECs irradiated with 2 Gy and 5 Gy at 24 h and 72 h after IR was conducted, focusing on processes related to EC activation. To validate the RNA sequencing results, immunofluorescence staining for proteins related to EC activation, including Stimulator of Interferon Response cGAMP Interactor 1 (STING), Nuclear factor kappa B (NF-κβ), and Vascular cell adhesion molecule 1 (VCAM-1), was performed. To validate the in vitro results, the response of TEC in vivo was analyzed using publicly available RNA sequencing data of TECs isolated from MC38 colon carcinoma irradiated with a single dose of 15 Gy. Finally, murine CT26 colon carcinoma tumors were immunofluorescently stained for STING and NF-κβ 24 and 48 h after IR with a clinically relevant fractionated regimen of 5 × 5 Gy. Results: Doses of 2, 4, 6, 8, and 10 Gy led to a dose-dependent decrease in proliferation and increased death of ECs. RNA sequencing analysis showed that the effects on the transcriptome of HUVECs were most pronounced 72 h after IR with 5 Gy, with 1014 genes (661 down-regulated and 353 up-regulated) being significantly differentially expressed. Irradiation with 5 Gy resulted in HUVEC activation, with up-regulation of the immune system and extracellular matrix genes, such as STING1 (log2FC = 0.81) and SELE (log2FC = 1.09), respectively; and down-regulation of cell cycle markers. Furthermore, IR led to the up-regulation of immune response- and extracellular matrix (ECM)-associated signaling pathways, including NF-κβ signaling and ECM–receptor interaction, which was also observed in the transcriptome of irradiated murine TECs in vivo. This was confirmed at the protein level with higher expressions of the EC activation-associated proteins STING, NF-κβ, and VCAM-1 in irradiated HUVECs and irradiated TECs in vivo. Conclusions: IR induces changes in ECs and TECs, supporting their activation in dose- and time-dependent manners, potentially contributing to the anti-tumor immune response, which may potentially increase the infiltration of immune cells into the tumor and thus, improve the overall efficacy of RT, especially in combination with immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Radiosensitivity and Radiotoxicity in Cancer)
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Review

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18 pages, 3506 KB  
Review
A Systems Approach to Radiation-Induced Cardiopulmonary Toxicity—A Narrative Literature Review Focusing on the Interdependence of the Heart and the Lung in Thoracic Radiotherapy
by Arezoo Modiri, Hairong Chen, Timm-Michael L. Dickfeld, Jeffrey D. Bradley and Amit Sawant
Cancers 2026, 18(13), 2099; https://doi.org/10.3390/cancers18132099 - 28 Jun 2026
Viewed by 466
Abstract
Thoracic radiotherapy, widely used in the treatment of mediastinal tumors, frequently exposes both the heart and lungs to ionizing radiation. While physiological interactions and shared vulnerability of the two organs have been known, heart and lung toxicities are assessed separately due to the [...] Read more.
Thoracic radiotherapy, widely used in the treatment of mediastinal tumors, frequently exposes both the heart and lungs to ionizing radiation. While physiological interactions and shared vulnerability of the two organs have been known, heart and lung toxicities are assessed separately due to the lack of systematic studies and computational models demonstrating their interactions. For instance, based on the most updated NCCN guidelines for esophageal cancer, radiation prescriptions for preoperative, postoperative, and definitive intents are 41.4–50.4 Gy. Cardiopulmonary toxicities are well-known treatment side-effects in this disease site. Therefore, an exhaustive multi-layered list of dose-limits for lung and heart protection are recommended by NCCN guidelines. However, no combined or conditional (on the other organ’s status) dose-limits are considered. Furthermore, while recommendations for dosimetric consideration of substructures during planning are becoming more common, whole heart and whole lung doses stay the main references for cardiac and pulmonary toxicities. A growing body of pre-clinical and clinical studies has investigated the interaction between cardiac and pulmonary systems in the context of radiation-induced toxicity. However, an analysis of cardiopulmonary system’s collective response to radiation—particularly in predictive modeling, toxicity assessment, and treatment planning—is currently lacking. Here, we review the harmful interdependent interactions between the heart and lungs, especially in cancer patients and in response to treatment. Then we study the existing cardiopulmonary system models and conclude with potential strategies to collect the required parameters for models applicable to radiotherapy. Full article
(This article belongs to the Special Issue Radiosensitivity and Radiotoxicity in Cancer)
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30 pages, 7506 KB  
Review
Tumor Treating Fields and the Glioblastoma Microenvironment: Mechanistic Convergences with Radiotherapy
by Flavio Donnini, Giuseppe Battaglia, Salvatore Chibbaro, Francesco Marampon, Giuseppe Minniti and Paolo Tini
Cancers 2026, 18(13), 2069; https://doi.org/10.3390/cancers18132069 - 25 Jun 2026
Viewed by 532
Abstract
Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15–20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase [...] Read more.
Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15–20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase III trial, their biological effects extend well beyond the canonical anti-mitotic mechanism and encompass extensive interactions with the GBM tumor microenvironment (TME). This review provides an integrated mechanistic analysis of TTFields–TME interactions in GBM, with a distinctive focus on their convergence with radiotherapy. We examine how TTFields activate innate immune sensing through cGAS/STING and AIM2 inflammasome pathways, drive immunogenic cell death, reprogram tumor-associated macrophages, and prime adaptive T cell responses. We further address TTFields effects on glioma stem cells, blood–brain barrier permeability, and intracellular signaling governing invasion, angiogenesis, and autophagy. Critically, we develop the mechanistic and clinical case for TTFields-radiotherapy combinations, highlighting convergent mechanisms of DNA repair impairment, mitotic catastrophe, and innate immune activation. Practical considerations for concurrent clinical implementation are discussed alongside a research agenda centered on optimal timing, hypofractionation, and predictive biomarkers. Available evidence—largely preclinical—suggests that TTFields may act as a TME-remodeling platform whose potential is most likely to be realized through mechanistically informed combinations. Full article
(This article belongs to the Special Issue Radiosensitivity and Radiotoxicity in Cancer)
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34 pages, 958 KB  
Review
From Cellular Radiosensitivity to Precision Radiotherapy: Integrating Functional Assays, Genomics, and Clinical Modeling
by Angeliki Gkikoudi, Sotiria Triantopoulou, Eygenia Markellou, Vasiliki Xynou, Spyridon N. Vasilopoulos, Marios Myronakis, Evagelia C. Laiakis, Kiki Theodorou, Georgia I. Terzoudi and Alexandros G. Georgakilas
Cancers 2026, 18(11), 1823; https://doi.org/10.3390/cancers18111823 - 2 Jun 2026
Viewed by 1462
Abstract
Background: Radiotherapy outcomes are determined by the balance between tumor control and normal tissue toxicity, both of which exhibit significant interpatient variability. While radiogenomic and molecular approaches have identified determinants of radiosensitivity, their predictive performance remains limited when used in isolation. Methods [...] Read more.
Background: Radiotherapy outcomes are determined by the balance between tumor control and normal tissue toxicity, both of which exhibit significant interpatient variability. While radiogenomic and molecular approaches have identified determinants of radiosensitivity, their predictive performance remains limited when used in isolation. Methods: This review provides a comprehensive synthesis of functional assays, genomic biomarkers, and integrative models used to assess radiosensitivity, including radiation-induced lymphocyte apoptosis (RILA), chromosomal radiosensitivity assays, micronucleus formation, γ-H2AX foci kinetics, comet assays, clonogenic survival, and patient-derived organoids, alongside genomic and molecular predictors of tumor response such as hypoxia signatures and gene expression-based models (e.g., RSI and GARD). Results: Functional assays provide direct phenotypic assessment of radiation response, capturing DNA repair capacity, chromosomal stability, apoptosis, and tissue regenerative potential, and have shown associations in several studies with normal tissue toxicity across clinical settings. Tumor radiosensitivity is influenced by intrinsic cellular factors and microenvironmental conditions, including hypoxia and genomic instability. Integrative approaches combining functional, genomic, and clinical data show increasing potential for improving predictive accuracy. Conclusions: Radiosensitivity should be considered a systems-level phenotype requiring multi-dimensional assessment. Conceptual frameworks that integrate tumor and normal tissue responses within a unified modeling approach, supported by measurable biological and clinical parameters, represent a promising direction for clinically actionable precision radiotherapy. The integration of functional assays with genomic and clinical modeling frameworks represents a promising strategy for advancing personalized radiotherapy and improving therapeutic outcomes. Full article
(This article belongs to the Special Issue Radiosensitivity and Radiotoxicity in Cancer)
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