• CRISPR/Cas9
• Cancer
• Chemoresistance
• Radioresistance

• CRISPR-Cas Systems
• Humans
• Neoplasms/genetics
• Neoplasms/therapy
• Neoplasms/radiotherapy
• Neoplasms/drug therapy
• Drug Resistance, Neoplasm/genetics
• Animals
• Gene Editing/methods
• Radiation Tolerance/genetics
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology

• PTEN
• apoptosis
• autophagy
• cell cycle arrest
• drug resistance
• epithelial-to-mesenchymal transition
• feedback loops
• lncRNA PTENP1
• miR-21
• senescence

• PTEN Phosphohydrolase/metabolism
• PTEN Phosphohydrolase/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Humans
• Epithelial-Mesenchymal Transition/genetics
• Drug Resistance, Neoplasm/genetics
• DNA Damage
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Gene Expression Regulation, Neoplastic
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/drug therapy
• Cell Line, Tumor
• Apoptosis/drug effects
• Apoptosis/genetics
• Signal Transduction

• 2023/14618-8 Fundação de Amparo à Pesquisa do Estado de São Paulo
• 925684/2023-00 Coordenação de Aperfeicoamento de Pessoal de Nível Superior
• 309817/2021-8 and 150960/2022-0 National Council for Scientific and Technological Development

• Breast cancer
• PI3K/mTOR pathway
• PKI-402
• radiosensitivity

• Humans
• Female
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Cell Proliferation/radiation effects
• Neoplasm Recurrence, Local
• TOR Serine-Threonine Kinases/metabolism
• Phosphoinositide-3 Kinase Inhibitors/pharmacology
• Breast Neoplasms/radiotherapy
• Breast Neoplasms/pathology
• Radiation Tolerance
• Apoptosis
• Cell Line, Tumor

• SUN1
• epithelial-mesenchymal transition (EMT)
• linker of nucleoskeleton and cytoskeleton (LINC) complex
• sublethal-dose X-ray

• Humans
• beta Catenin/metabolism
• X-Rays
• Epithelial-Mesenchymal Transition
• Mechanotransduction, Cellular
• Cytoskeleton/metabolism
• Nuclear Matrix/metabolism
• Cell Movement
• Cell Line, Tumor
• Cadherins/metabolism

• Japan Society for the Promotion of Science

Esophageal squamous cell carcinoma (ESCC) is causing a high mortality rate due to the lack of efficient early prognosis markers and suitable therapeutic regimens. The prognostic role of genes responsible for the acquisition of radioresistance in ESCC has not been fully elucidated.

To establish a prognostic model by studying gene expression patterns pertinent to radioresistance in ESCC patients.

Datasets were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The edgeR, a Bioconductor package, was used to analyze mRNA expression between different groups. We screened genes specifically responsible for radioresistance to estimate overall survival. Pearson correlation analysis was performed to confirm whether the expression of those genes correlated with each other. Genes contributing to radioresistance and overall survival were assessed by the multivariate Cox regression model through the calculation of βi and risk score using the following formula: .

We identified three prognostic mRNAs (cathepsin S [CTSS], cluster of differentiation 180 [CD180], and SLP adapter and CSK-interacting membrane protein [SCIMP]) indicative of radioresistance. The expression of the three identified mRNAs was related to each other (r > 0.70 and P < 0.05). As to 1-year and 3-year overall survival prediction, the area under the time-dependent receiver operating characteristic curve of the signature consisting of the three mRNAs was 0.716 and 0.841, respectively. When stratifying patients based on the risk score derived from the signature, the high-risk group exhibited a higher death risk and shorter survival time than the low-risk group (P < 0.0001). Overall survival of the low-risk patients was significantly better than that of the high-risk patients (P = 0.018).

We have developed a novel three-gene prognostic signature consisting of CTSS, CD180, and SCIMO for ESCC, which may facilitate the prediction of early prognosis of this malignancy.

• Esophageal squamous cell carcinoma
• CTSS
• CD180
• SCIMP
• Radioresistance
• TNM stage
• Prognosis

• Chemotherapy
• Esophageal squamous cell carcinoma
• PD-L1
• PTEN
• Radiotherapy

• B7-H1 Antigen/genetics
• B7-H1 Antigen/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Programmed Cell Death 1 Receptor/genetics

• cancer
• chemoresistance
• molecular mechanisms
• radioresistance
• targeted therapy

• National Natural Science Foundation of China
• Fundamental Research Funds for the Central Universities
• National Key Research and Development Program of China

• Radiation therapy
• anti-cancer immunity
• inflammatory cytokines
• protumoral response

High-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40–47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT.

An in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X‑ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST‑1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay).

The FUS intensities of 213 (1.147 MHz) and 225 W/cm² (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells.

Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage.

The online version of this article (10.1007/s00066-021-01774-5) contains supplementary material, which is available to authorized users.

• Apoptosis
• DNA double-strand breaks
• FUS
• Hyperthermia
• Radiation therapy

• EMT
• Mechanism
• Non-coding RNAs
• Radioresistance
• Signaling pathway

• biomarkers
• microRNA
• prostate cancer
• radiation resistance
• radiotherapy

• Animals
• Biomarkers, Tumor/genetics
• Gene Expression Regulation, Neoplastic/radiation effects
• Humans
• Male
• MicroRNAs/genetics
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/radiotherapy
• Radiation, Ionizing

• Ligue Contre le Cancer
• Conseil Régional des Pays de la Loire
• Cancéropôle Grand Ouest
• Terry Fox Foundation
• Sunnybrook Research Institute (CA)
• Movember Foundation
• Telus motorcycle ride for dad

Radioresistance in response to radiotherapy leads to cancer recurrence and poor survival in hypopharyngeal carcinoma patients. Previous studies indicate that ionizing radiation (IR) can induce epithelial–mesenchymal transition (EMT) that promotes the radioresistance, migration and invasiveness of tumors. The aim of this study was to explore the role of Snail in EMT and acquired radioresistance in hypopharyngeal carcinoma.

Radioresistance human hypopharyngeal carcinoma cells (FaduRR) were previously established from the Fadu cell line. Radiosensitivity was measured by colony forming assay. Western blot and Quantitative real-time PCR were used to detect the expression of EMT phenotypes and AKT/GSK-3β/Snail signaling pathway related proteins in Fadu+4Gy and FaduRR cells. Transwell and wound-healing assays were used to measure cell migration and invasiveness. EMT-related proteins and Snail expression were assessed in 80 hypopharyngeal carcinoma patient samples from radiosensitive and radioresistance groups using immunohistochemistry. Snail was silenced to evaluate its effects on EMT, radioresistance, migration, and invasiveness of FaduRR cells.

The molecular characteristics of EMT were observed following radiation treatment, with migration, invasiveness and radioresistance enhanced in Fadu+4Gy and FaduRR cells. Moreover, we demonstrated that IR-induced EMT by activating the AKT/GSK-3β/Snail signaling pathway and that Snail silencing reversed EMT and attenuated radioresistance in FaduRR cells. Significant differences in EMT-related proteins and Snail expression were observed between radiosensitive and resistant group.

We demonstrate that IR can trigger EMT and enhance the migration, invasiveness, and radioresistance of FaduRR cells through the AKT/GSK-3β/Snail axis. Snail silencing could attenuate these effects and represents a novel therapeutic target for EMT-induced radioresistance in hypopharyngeal carcinoma.

• AKT/GSK-3β/Snail
• Snail
• epithelial-mesenchymal transition
• hypopharyngeal carcinoma
• radioresistance

• Nasopharyngeal carcinoma (NPC)
• epithelial-mesenchymal transition (EMT)
• necroptosis

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.

• 3D culture
• Matrigel
• breast cancer outcomes
• cancer stem cells
• inhibitors
• irradiation
• matrix metalloproteases
• radiotherapy
• stemness phenotype
• targeted treatment

• FIR
• IFN-γ
• anticancer
• lung cancer
• signaling

Esophageal squamous cell carcinoma (ESCC) cells are heterogeneous, easily develop radioresistance, and recur. Single-cell RNA-seq (scRNA-seq) is a next-generation sequencing method that can delineate diverse gene expression profiles of individual cells and mining their heterogeneous behaviors in response to irradiation. Our aim was using scRNA-seq to describe the difference between parental cells and cells that acquired radioresistance, and to investigate the dynamic changes of the transcriptome of cells in response to FIR.

We sequenced ESCC cell lines KYSE180 with and without fractionated irradiation (FIR). A total of 218 scRNA-seq libraries were obtained from 88 cells exposed to 12 Gy (KYSE-180-12 Gy), 89 exposed to 30 Gy (KYSE-180-30 Gy), and 41 parental KYSE-180 cells not exposed to FIR. Dynamic gene expression patterns were determined by comprehensive consideration of genes and pathways. Biological experiments showed that KYSE-180 cells became radioresistant after FIR. PCA analysis of scRNA-seq data showed KYSE-180, KYSE-180-12 Gy and KYSE-180-30 Gy cells were discrete away from each other. Two sub-populations found in KYSE-180-12 Gy and only one remained in KYSE-180-30 Gy. This sub-population genes exposure to FIR through 12 Gy to 30 Gy were relevant to the PI3K-AKT pathway, pathways evading apoptosis, tumor cell migration, metastasis, or invasion pathways, and cell differentiation and proliferation pathways. We validated DEGs, such as CFLAR, LAMA5, ITGA6, ITGB4, and SDC4 genes, in these five pathways as radioresistant genes in bulk cell RNA-seq data from ESCC tissue of a ESCC patient treated with radiotherapy and from KYSE-150 cell lines.

Our results delineated the divergent gene expression patterns of individual ESCC cells exposure to FIR, and displayed genes and pathways related to development of radioresistance.

The online version of this article (10.1186/s12864-019-5970-0) contains supplementary material, which is available to authorized users.

• Esophageal squamous cell carcinoma
• Gene expression
• Radioresistance
• Single-cell RNA-seq
• Transcriptome

Ionizing radiation (IR) is widely used for treating nasopharyngeal carcinoma (NPC). However, recent studies indicate that IR can also promote the migration and invasion of malignant tumors. Phosphatase 1 nuclear-targeting subunit (PNUTS), a novel interacting protein, was recently demonstrated to be involved in tumorigenesis and metastasis formation. This protein was hypothesized to take part in IR-induced migration and invasion in NPC cells in this study.

Western blotting was used to detect how PNUTS was expressed in NPC cells with or without IR treatment. Wound-healing and Transwell assays were used to measure cell migration and invasion. Quantitative real-time PCR and Western blotting were used to determine the expression levels of PNUTS and epithelial–mesenchymal transition (EMT) proteins, respectively, after CNE-2 cells were infected with an adenovirus vector, ad-PNUTS, or transfected with PNUTS-specific siRNA. Finally, the expression levels of PI3K/AKT signaling-related proteins were detected by Western blotting.

IR significantly promoted PNUTS expression and the migration and invasion in CNE-2 cells. Moreover, after exposure to IR, expression of the mesenchymal markers N-cadherin and vimentin increased, while that of the epithelial marker E-cadherin decreased. Silencing PNUTS remarkably attenuated IR-induced increases in cell migration and invasion and reversed the EMT process. Additionally, the overexpression of PNUTS restored the mobility and invasiveness of CNE-2 cells, which regained EMT characteristics. Furthermore, we found that PNUTS regulated IR-induced EMT via the PI3K/AKT signaling pathway.

Our research illustrates a relationship between PNUTS and IR-induced cell migration and invasion and provides a novel therapeutic target for preventing radiotherapy-induced metastasis in NPC patients.

• EMT
• NPC
• PI3K/AKT pathway
• PNUTS
• ionizing radiation

• Alzheimer’s disease
• agomelatine
• oxidative stress
• tau hyperphosphorylation

Esophageal cancer is the eighth most common form of cancer worldwide, and esophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer that arises from epithelial cells of the esophagus. Local lymph node metastasis (LNM) is a typical sign of failure for ESCC clinical treatments, and a link has been established between LNM and the aberrant expression of specific biomarkers. In this review, we summarize what is known about nine factors significantly associated with LNM in ESCC patients: phosphatase and tensin homolog (PTEN), mucin 1, vascular endothelial growth factor-C, tumor necrosis factor alpha-induced protein 8 (TNFAIP8), Raf-1 kinase inhibitory protein, stathmin (STMN1), metastasis-associated protein 1, caveolin-1, and interferon-induced transmembrane protein 3. The function of these nine proteins involves four major mechanisms: tumor cell proliferation, tumor cell migration and invasion, epithelium–mesenchymal transition, and chemosensitivity. The roles of PTEN, STMN1, and TNFAIP8 involve at least two of these mechanisms, and we suggest that they are possible biomarkers for predicting LNM in ESCC. However, further retrospective research into PTEN, STMN1, and TNFAIP8 is needed to test their possibilities as indicators.

• Lymph node metastasis
• biomarkers
• chemosensitivity
• epithelial–mesenchymal transition
• esophageal squamous cell carcinoma
• invasion
• migration
• proliferation

Radioresistance is a substantial barrier to success in cancer management. A number of molecular mechanisms support radioresistance. We have shown experimentally that the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3 may modulate the state of radiosensitivity of tumor cells. Specifically, tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T₄), can reduce radioresistance in cancer cells. In this review, we list a number of intrinsic signal transduction molecules and other host factors that have been reported to support/induce radioresistance in cancer cells and that are also subject to control by T₄ through actions primarily initiated at integrin αvβ3. Additional preclinical evidence is needed to support these radioresistance-relevant actions of thyroid hormone.

• AKT
• L-thyroxine (T4)
• STAT3
• epithelial-mesenchymal transition (EMT)
• integrin open configuration

• Cell Adhesion/radiation effects
• Cell Line, Tumor
• Cell Movement/radiation effects
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Humans
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Nerve Tissue Proteins/antagonists & inhibitors
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• RNA Interference
• RNA, Small Interfering/metabolism
• Receptors, Immunologic/antagonists & inhibitors
• Receptors, Immunologic/genetics
• Receptors, Immunologic/metabolism
• Vimentin/genetics
• Vimentin/metabolism
• X-Rays
• Roundabout Proteins

• BIOX Stiftung

• Cancer
• Invasion
• Metastasis
• Radiation
• Radiotherapy

• EMT
• Esophageal cancer
• PI3K/AKT
• PTEN
• Radioresistance
• Simvastatin

• AKT
• Actinin-4
• Breast cancer
• Epithelial-mesenchymal transition
• Invasion
• Radioresistance

The acquisition of radioresistance by esophageal squamous carcinoma (ESC) cells during radiotherapy may lead to cancer recurrence and poor survival. Previous studies have demonstrated that ionizing radiation (IR) induces epithelial–mesenchymal transition (EMT) of ESC cells accompanied by increased migration, invasion, and radioresistance. However, the underlying molecular mechanisms of IR-induced EMT and radioresistance are not well established, hampering the development of potential solutions. To address this issue, we investigated the role of the IL-6/STAT3/TWIST signaling pathway in IR-induced EMT. We found not only the pathway was activated during IR-induced EMT but also STAT3 inhibition or Twist depletion reversed the EMT process and attenuated radioresistance. These results improve our understanding of the underlying mechanisms involved in IR-induced EMT and suggest potential interventions to prevent EMT-induced acquisition of radioresistance.

• EMT
• IL-6/STAT3/TWIST pathway
• radioresistance

• ncRNA
• tDR
• tRF
• tRNA fragments
• tsRNA

• A549 Cells
• Case-Control Studies
• HEK293 Cells
• Humans
• Neoplasms/metabolism
• Oncogenes
• RNA, Small Untranslated/metabolism

• U01 CA196383 NCI NIH HHS
• U01 CA166905 NCI NIH HHS
• R35 CA197582 NCI NIH HHS
• R35 CA197706 NCI NIH HHS
• R01 CA190740 NCI NIH HHS
• P01 CA082834 NCI NIH HHS

• Esophageal cancer
• radioresistance
• radiosensitive biomarker
• targeted therapy
• tumor-associated microenvironment (TAM)

• CD90
• Cancer stem cells (CSCs)
• esophageal squamous cell carcinoma (ESCC)
• radiation sensitivity

Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors—including Snail, HIF-1, ZEB1, and STAT3—that are activated by signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.

• Cancer stem cells
• Epithelial-mesenchymal transition
• Metastasis
• Oncogenic metabolism
• Radioresistance
• Radiotherapy
• Reactive oxygen species
• Snail
• Tumour microenvironment

• Apoptosis/drug effects
• Apoptosis/radiation effects
• Blotting, Western
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Adhesion/drug effects
• Cell Adhesion/radiation effects
• Cell Movement/drug effects
• Cell Movement/radiation effects
• Cell Proliferation/drug effects
• Cell Proliferation/radiation effects
• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/radiation effects
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/pathology
• Fluorescent Antibody Technique
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/radiation effects
• Humans
• Hypoglycemic Agents/pharmacology
• Metformin/pharmacology
• Neoplasm Invasiveness
• Phenotype
• Phosphorylation/drug effects
• Phosphorylation/radiation effects
• Signal Transduction/drug effects
• Signal Transduction/radiation effects
• Smad2 Protein/metabolism
• Smad3 Protein/metabolism
• Transforming Growth Factor beta/metabolism
• Tumor Cells, Cultured
• X-Rays

• esophageal squamous cell carcinoma
• epithelial mesenchymal transition
• histone deacetylase
• stem cell
• valproic acid

• Anticonvulsants/pharmacology
• Apoptosis/drug effects
• Apoptosis/radiation effects
• Blotting, Western
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/radiotherapy
• Cell Movement/drug effects
• Cell Movement/radiation effects
• Cell Proliferation/drug effects
• Cell Proliferation/radiation effects
• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/radiation effects
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/radiotherapy
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/radiation effects
• Tumor Cells, Cultured
• Valproic Acid/pharmacology
• X-Rays

Recent advancement in the radiotherapy technology has allowed conformal delivery of high doses of ionizing radiation precisely to the tumors while sparing large volume of the normal tissues, which have led to better clinical responses. Despite this technological advancement many advanced tumors often recur and they do so within the previously irradiated regions. How could tumors recur after receiving such high ablative doses of radiation? In this review, we outlined how radiation can elicit anti-tumor responses by introducing some of the cytokines that can be induced by ionizing radiation. We then discuss how tumor hypoxia, a major limiting factor responsible for failure of radiotherapy, may also negatively impact the anti-tumor responses. In addition, we highlight how there may be other populations of immune cells including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that can be recruited to tumors interfering with the anti-tumor immunity. Finally, the impact of irradiation on tumor hypoxia and the immune responses according to different radiotherapy regimen is also delineated. It is indeed an exciting time to see that radiotherapy is being combined with immunotherapy in the clinic and we hope that this review can add an excitement to the field.

• Cancer
• Hypoxia
• Immune system
• Radiotherapy

• cancer stem cells
• dedifferentiation
• epithelial-mesenchymal transition
• non-stem cancer cells
• radioresistance
• radiotherapy

• Epithelial–mesenchymal transition
• Esophageal carcinoma
• Radiotherapy
• Recombinant human endostatin
• Vasculogenic mimicry

• EGFR-AS1
• Epidermal growth factor receptor
• Growth hormone receptor
• Hepatocellular carcinoma
• Long noncoding RNA