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L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial
Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.
- Frank A. Giordano
- , Julian P. Layer
- & Michael Hölzel
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Article
| Open Access
Chiral coordination polymer nanowires boost radiation-induced in situ tumor vaccination
Radiation-induced tumor vaccination is insufficient to elicit robust antitumor immune response. Here they combine chiral vidarabine monophosphate-gadolinium nanowires with immune checkpoint blockade therapy to synergistically induce antitumor immunity.
Reviewer recognition:
- Zhusheng Huang
- , Rong Gu
- & Ahu Yuan
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Article
| Open Access
Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
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Article
| Open Access
Heavy-to-light electron transition enabling real-time spectra detection of charged particles by a biocompatible semiconductor
New detector materials are crucial for radiation beam monitoring in dosimeters and X-ray imaging. The authors report a solution-grown biocompatible organic single crystalline semiconductor for real-time spectral detection of charged particles with single-particle sensitivity, X-ray detection and imaging.
- Dou Zhao
- , Ruiling Gao
- & Yadong Xu
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Article
| Open Access
Epigenetic reprogramming shapes the cellular landscape of schwannoma
Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.
- S. John Liu
- , Tim Casey-Clyde
- & David R. Raleigh
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Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial
The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc analysis.
- Nasser K. Altorki
- , Zachary H. Walsh
- & Timothy E. McGraw
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Article
| Open Access
Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells
An increasing number of preclinical and clinical studies have investigated the antitumor efficacy of combined radiotherapy and immunotherapy. Here the authors report that low-dose radiotherapy enhances the antitumor effect of dual VEGFA and PD-L1 blockade in preclinical models of hepatocellular carcinoma.
- Siqi Li
- , Kun Li
- & Yang Yang
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Article
| Open Access
Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy
Radiotherapy (RT) sensitizers have been used to overcome tumor hypoxia and improve response to RT. Here the authors design and characterize a pH and oxygen sensitive nano-molecular probe for imaging-guided cancer radiotherapy.
- Rong A
- , Haoyu Wang
- & Xilin Sun
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Article
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Myoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy
Researchers have been working on radiosensitizers to improve radiotherapy efficacy. Here the authors generate gadolinium nanotexaphyrins (Gd-NTs) that self-assemble and further load it with myoglobulin to relieve hypoxia, improve radiosensitization effects of Gd-coordinated Texaphyrin, and suppress tumor recurrence.
- Xiaotu Ma
- , Xiaolong Liang
- & Fan Wang
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Article
| Open Access
Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.
- Arta M. Monjazeb
- , Megan E. Daly
- & Karen Kelly
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Article
| Open Access
Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors
Radiation therapy (RT) has been shown to improve responses to immunotherapy in preclinical cancer models, but deep responses in patients are still rare. Here the authors provide immunological insights into the response to RT and CTLA4 inhibition in tumor bearing mice and show that agonistic CD40 therapy improves response to the combination of RT and immune checkpoint inhibition.
- Nils-Petter Rudqvist
- , Maud Charpentier
- & Sandra Demaria
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Article
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Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice
IL-2 complexes (IL-2c) which are IL-2 complexed with anti-IL-2 can be used to promote T cell function. Here authors use IL2c in addition to checkpoint inhibitors and irradiation to increase anti-tumour T cell responses and promote tumour rejection in mouse cancer models.
- Kateryna Onyshchenko
- , Ren Luo
- & Gabriele Niedermann
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| Open Access
Localized nuclear reaction breaks boron drug capsules loaded with immune adjuvants for cancer immunotherapy
Boron neutron capture therapy (BNCT) is a type of radiotherapy that induces cell damage through a localized nuclear reaction. Here the authors describe the design of a carborane-based covalent organic framework as a boron capsule loaded with immune adjuvants for concurrent BNCT and immunotherapy, promoting anti-tumour immune responses in preclinical cancer models.
- Yaxin Shi
- , Zhibin Guo
- & Zhibo Liu
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Article
| Open Access
TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models
The molecular mechanisms determining the response to radiotherapy remain incompletely understood. Here, the authors demonstrate that the E3 ubiquitin ligase and intracellular Fc receptor, TRIM21, impairs CD8+ T cell responses in nasopharyngeal carcinoma tumour models following ionizing radiation.
- Jun-Yan Li
- , Yin Zhao
- & Na Liu
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Article
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Stem cell–nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy
Gadolinium-neutron capture therapy (Gd-NCT) in glioblastoma shows promise but is limited by toxicity and short-half life in the brain. Here, the authors present a magnetised stem cell-nanoparticle system to facilitate brain penetrance of Gd-NCT and demonstrate its utility in an orthotopic rat glioblastoma model.
- Yen-Ho Lai
- , Chia-Yu Su
- & San-Yuan Chen
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Article
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Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors
Neck dissection and/or elective nodal irradiation (ENI) are commonly performed in patients with head and neck squamous cell carcinoma (HNSCC) to minimize local and regional recurrence. However, here the authors show that ENI blunts the immune response to combined radiation and immunotherapy, increasing local and distant tumor growth in HNSCC preclinical models.
- Laurel B. Darragh
- , Jacob Gadwa
- & Sana D. Karam
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Comprehensive and clinically accurate head and neck cancer organs-at-risk delineation on a multi-institutional study
Accurate organ at risk (OAR) segmentation is critical to reduce the radiotherapy post-treatment complications. Here, the authors develop an automated OAR segmentation system to delineate a comprehensive set of 42 H&N OARs.
- Xianghua Ye
- , Dazhou Guo
- & Tsung-Ying Ho
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Article
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Breaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application
Triggered therapeutics are of interest but currently suffer from limited penetration depth of light sources. Here, the authors report on the development of a system, called radioswitch, that uses ionising irradiation to switch an azobenzene modified drug to an active form for deep tissue triggered therapeutic application.
- Alban Guesdon-Vennerie
- , Patrick Couvreur
- & Guillaume Bort
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Article
| Open Access
Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy
Monomethyl auristatin (MMAE), also known for its radiosensitizer properties, is a common antibody drug conjugate used for cancer therapy. Here the authors show that, in combination with radiotherapy, tumor-directed antibodies or peptides conjugated to MMAE promote anti-tumor immune responses, improving response to checkpoint inhibitors in preclinical cancer models.
- Dina V. Hingorani
- , Michael M. Allevato
- & Sunil J. Advani
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Article
| Open Access
Catalytic activity imperative for nanoparticle dose enhancement in photon and proton therapy
Nanoparticles have recently received attention in radiation therapy since they can act as radioenhancers. In this article, the authors report on the dose enhancement capabilities of a series of nanoparticles based on their metal core composition and beam characteristics, obtaining designing criteria for their optimal performance in specific radiotreatments.
- Lukas R. H. Gerken
- , Alexander Gogos
- & Inge K. Herrmann
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Article
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MRNIP condensates promote DNA double-strand break sensing and end resection
The MRN complex is a critical sensor and processor of DNA double-strand breaks (DSBs). Here, the authors show that MRNIP forms liquid-like condensates to accelerate the MRN-mediated sensing and end resection of DSB, thereby promoting DSB repair.
- Yun-Long Wang
- , Wan-Wen Zhao
- & Xiang-Bo Wan
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Article
| Open Access
Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion
Acquired radioresistance is a challenge for the cure of glioblastoma. Here, the authors show that radioresistant glioblastoma boosts mitochondrial fatty acid oxidation that fuels cell proliferation and induces immunosuppression via CD47 mediated anti-phagocytosis. Inhibition of FAO by etomoxir combined with anti-CD47 antibodies sensitizes glioblastoma to radiotherapy.
- Nian Jiang
- , Bowen Xie
- & Jian Jian Li
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Article
| Open Access
Microalgae-based oral microcarriers for gut microbiota homeostasis and intestinal protection in cancer radiotherapy
Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Here the authors use a natural microalga to readily construct an oral delivery system to achieve effective radioprotection for the small intestine.
- Dongxiao Zhang
- , Danni Zhong
- & Min Zhou
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Article
| Open Access
USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma
Radiotherapy is the mainstay treatment for nasopharyngeal carcinoma (NPC). Here the authors show that the deubiquitinase, USP44, increases radiosensitivity of NPC cells by promoting the degradation of Ku80, and thus enhancing the levels of DNA damage.
- Yang Chen
- , Yin Zhao
- & Na Liu
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Article
| Open Access
Theranostic near-infrared-IIb emitting nanoprobes for promoting immunogenic radiotherapy and abscopal effects against cancer metastasis
Hypoxia and immunosuppression contribute to tumor resistance to radiotherapy (RT). Here the authors design a nanoprobe based on NIR-IIb emitting quantum dots for image-guided RT and modified with catalase to relieve hypoxia in the tumor microenvironment, enhancing the precision and efficacy of RT and promoting anti-tumor immune responses.
- Hao Li
- , Meng Wang
- & Zhi-Jun Sun
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Article
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Induction chemotherapy followed by definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: a randomized phase II trial
The benefit of induction chemotherapy before definitive chemoradiotherapy (CRT) for patients with esophageal cancer is still uncertain. The results of this phase II randomized trial show that the addition of induction chemotherapy to CRT does not improve the response rate or survival of patients with unresectable esophageal squamous cell carcinoma.
- Shiliang Liu
- , Liling Luo
- & Mian Xi
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Article
| Open Access
Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance
The molecular mechanisms underlying cancer cell radioresistance need to be elucidated. In this study, the authors show that the microRNA biogenesis factor DGCR8 is stabilized by USP51 and ATM upon irradiation and by consequence it promotes the repair of DNA double-strand breaks and radioresistance by recruiting RNF168 to sites of damage.
- Qinglei Hang
- , Liyong Zeng
- & Li Ma
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| Open Access
Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy
Signal-regulatory protein α (SIRPα) is an inhibitory receptor expressed by myeloid cells. Here the authors show that, in preclinical cancer models, resistance to radiotherapy (RT) observed in wild-type mice is overcome in Sirpα-deficient mice, providing evidences that RT-activated Sirpα-deficient macrophages promote T-cell mediated anti-tumor immune responses.
- Zhen Bian
- , Lei Shi
- & Yuan Liu
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Article
| Open Access
Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer
Radioresistance remains a challenge in the treatment of bladder cancer. In this study, the authors show in mice that radiation increases deposits of neutrophil extracellular traps (NETs) via a TLR4-dependent mechanism and that NETs-targeting strategies can improve the response to radiotherapy.
- Surashri Shinde-Jadhav
- , Jose Joao Mansure
- & Wassim Kassouf
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Article
| Open Access
STING enhances cell death through regulation of reactive oxygen species and DNA damage
The endoplasmic reticulum-localized adaptor STING regulates the innate immune response through its ability to sense DNA damage. Here the authors reveal that STING functions as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
- Thomas J. Hayman
- , Marta Baro
- & Joseph N. Contessa
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Article
| Open Access
A hybrid semiconducting organosilica-based O2 nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy
Tumor hypoxia is a major limitation in radiotherapy, and strategies to address this often fail due to high oxygen consumption. Here, the authors report a nanomaterial assembly for the simultaneous reduction in mitochondrial respiration and to supply oxygen to potentiate radiotherapy.
- Wei Tang
- , Zhen Yang
- & Xiaoyuan Chen
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Article
| Open Access
Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells
The emergence of tumour adaptive radioresistance can limit the success of radiation therapy and immunotherapy in breast cancer. In this study, the authors demonstrate that CD47 and HER2 are coordinating in tumor response to radiation and that co-blockage of both receptors can eliminate radiorestistant breast cancer cells.
- Demet Candas-Green
- , Bowen Xie
- & Jian Jian Li
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Article
| Open Access
FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy
Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy.
- Jae Hong Im
- , Jon N. Buzzelli
- & Ruth J. Muschel
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Article
| Open Access
Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation
Abscopal responses in patients and preclinical models following radiation therapy are rare. Here the authors show that, in murine tumor models, reducing adrenergic stress or β2-adrenergic receptor signalling not only improves control of the irradiated tumor but significantly increases abscopal events.
- Minhui Chen
- , Guanxi Qiao
- & Elizabeth A. Repasky
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Article
| Open Access
An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases
Successful anticancer immunotherapy should induce robust systemic immunity against metastases. Here, the authors engineer an inhalable nano-STING agonist, which synergizes with fractionated radiation to control lung metastases and confers long-term systemic antitumor immunity in mice.
- Yang Liu
- , William N. Crowe
- & Dawen Zhao
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Article
| Open Access
Tumor-reprogrammed resident T cells resist radiation to control tumors
Lymphocytes are considered one of the most radiosensitive cell types in the body. Here the authors show that unlike circulating lymphocytes, tumor-infiltrating T cells survive therapeutic doses of irradiation, remaining functional and contributing to radiotherapy induced anti-tumor immunity.
- Ainhoa Arina
- , Michael Beckett
- & Ralph R. Weichselbaum
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Article
| Open Access
Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Radiation damage causes DNA foci to form and senescence, causing ulcers. Here, the authors show that a naturally occurring adenosine analogue, cordycepin, prevents cell senescence via an increase in AMPK/NRF2, so blocking ulcers caused by radiation on skin/intestine/tongue damage in rodents.
- Ziwen Wang
- , Zelin Chen
- & Chunmeng Shi
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Article
| Open Access
Generic synthesis of small-sized hollow mesoporous organosilica nanoparticles for oxygen-independent X-ray-activated synergistic therapy
A common failure of many cancer treatments is attributed to the resistance imparted by tumour hypoxia. Here, the authors report on the generic synthesis of small-sized hollow mesoporous organosilica nanoparticles which are designed for oxygen-independent X-ray-activated synergistic therapy.
- Wenpei Fan
- , Nan Lu
- & Xiaoyuan Chen
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Article
| Open Access
Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6+ cancer cell and macrophage polarization
Radiotherapy is the main treatment for most cancer, but it is unclear if targeting tumour vasculature can enhance tumour radiosensitivity. Here, the authors show that tumour endothelial-mesenchymal transition after radiotherapy leads to proliferation of radioresistant CSCs and tumour associated macrophages polarization.
- Seo-Hyun Choi
- , A-Ram Kim
- & Yoon-Jin Lee
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Article
| Open Access
Stromal PTEN determines mammary epithelial response to radiotherapy
The tumor microenvironment influences tumor progression. Here the authors show that lack of stromal PTEN phosphatase induces DNA repair defects in the neighboring mammary gland epithelial cells via hyperactivation of EGF-receptor signaling, resulting in higher radiation-induced DNA damage and hyperplasia.
- Gina M. Sizemore
- , Subhasree Balakrishnan
- & Michael C. Ostrowski
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Article
| Open Access
ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
Following double-strand break a cascade of events leads to the recruitment of repair factors to damaged sites. Here the authors identify ZNF506 as a key factor that mediates post-translational modification changes in H2AX affecting the DNA damage response.
- Somaira Nowsheen
- , Khaled Aziz
- & Zhenkun Lou
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Article
| Open Access
Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
Radionuclides that emit alpha particles (charged helium nuclei) are currently used clinically to treat cancers including prostate cancer. Here, the authors combine a humanized antibody to an alpha particle emitter, specifically to target a downstream effector of the androgen receptor and create a feed forward loop that increases the therapeutic efficacy.
- Michael R. McDevitt
- , Daniel L. J. Thorek
- & David Ulmert
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Article
| Open Access
DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity
Trex1 is an exonuclease that degrades cytosolic DNA and has been associated with modulation of interferon responses in autoimmunity and viral infections. Here, the authors show that Trex1 attenuates the immunogenicity of cancer cells treated with high radiation doses by degrading cytosolic DNA and preventing the activation of interferon response.
- Claire Vanpouille-Box
- , Amandine Alard
- & Sandra Demaria
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Article
| Open Access
Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize
Drugs that sensitize tumour cells to ionizing radiation are prized because they can overcome resistance to radiotherapy. Here, the authors show that anti-tubulin drugs conjugated to cetuximab or trastuzumab can radiosensitize EGFR- or HER2-expressing tumors by increasing DNA damage and cell death due to ionizing radiation.
- Stephen R. Adams
- , Howard C. Yang
- & Sunil J. Advani
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Article
| Open Access
A genetic basis for the variation in the vulnerability of cancer to DNA damage
The variability in patient response to radiation treatment is difficult to predict. Here, using more than 500 cell lines the authors measure response to radiation exposure and a large panel of compounds, and show that response can be predicted by genetic alterations of the cells.
- Brian D. Yard
- , Drew J. Adams
- & Mohamed E. Abazeed
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Article
| Open Access
LIG4 mediates Wnt signalling-induced radioresistance
The Wnt/β-catenin signalling pathway contributes to radio resistance in intestinal stem cells but the underlying mechanism is currently unknown. In this study, the authors demonstrate that LIG4, a DNA ligase involved in the DNA repair process, is a direct target of β-catenin and it specifically mediates non-homologous end joining repair in colorectal cancer cells.
- Sohee Jun
- , Youn-Sang Jung
- & Jae-Il Park
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Article
| Open Access
Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis
Radiotherapy can induce fibrosis in cancer patients, limiting its use in clinical settings. Here, the authors identify a differentially methylated enhancer of the lipid kinase DGKA in fibroblasts from breast cancer patients developing fibrosis after radiotherapy and they show that DGKA inhibition affects lipid homeostasis and reduces pro-fibrotic fibroblast activation.
- Christoph Weigel
- , Marlon R. Veldwijk
- & Odilia Popanda
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| Open Access
Kinase-independent role for CRAF-driving tumour radioresistance via CHK2
Tumors hijack cellular pathways to evade the effects of cancer therapy. Here, Advaniet al. show that DNA damage-induced phosphorylation of CRAF Serine 338 triggers DNA repair by recruiting CHK2, highlighting a role for CRAF independent from its canonical function as a kinase.
- Sunil J. Advani
- , Maria Fernanda Camargo
- & David A. Cheresh
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Numerical chromosomal instability mediates susceptibility to radiation treatment
Ionizing radiations (IRs) cause widespread genomic damage and can, through unknown mechanisms, lead to changes in chromosome numbers by perturbing the cells undergoing mitosis. Here, the authors investigate the potential mechanism behind the increased susceptibility of mitotic cells to IRs.
- Samuel F. Bakhoum
- , Lilian Kabeche
- & Duane A. Compton
Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy