{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:53:32Z","timestamp":1791640412176,"version":"4.3.4"},"reference-count":146,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    Targeted radionuclide therapy (TRT) delivers ionizing radiation directly to cancer cells through radio molecules that bind tumor-associated targets. Clinically successful examples include somatostatin receptor-directed TRT for neuroendocrine tumors, and prostate specific membrane antigen-targeted TRT for prostate cancer. Despite these advances, therapeutic efficacy remains limited by sublethal tumor doses, heterogeneous intratumoral uptake, and intrinsic radioresistance. A major challenge in improving TRT is the continued reliance on radiobiological concepts derived from external beam radiotherapy (EBRT). In contrast to EBRT, TRT is characterized by prolonged exposure times, low and variable dose rates, heterogeneous energy deposition, and radiation qualities ranging from low-linear energy transfer (LET) \u03b2\n                    <jats:sup>-<\/jats:sup>\n                    - particles to high-LET \u03b1-particles, resulting in distinct biological stress profiles that cannot be fully predicted from EBRT-based knowledge. This review summarizes the radiobiological properties that distinguish TRT from EBRT and describes how these features influence DNA damage induction and downstream cellular stress responses. Key cellular outcomes, including apoptosis, senescence, and alternatively regulated cell death pathways are discussed in relation to how dose rate kinetics and LET affect their timing and magnitude. By integrating concepts from radiation physics, DNA damage signaling, and cell fate mechanisms, this review highlights areas where mechanistic understanding remains limited and points to opportunities for refining TRT. A deeper understanding of these processes will support rational treatment design and help develop strategies that enhance tumor sensitivity while minimizing normal-tissue toxicity.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1880443","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:23:03Z","timestamp":1784262183000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Cellular responses to targeted radionuclide therapy: rethinking radiobiology under continuous low dose rates"],"prefix":"10.3389","volume":"16","author":[{"given":"Pleun A.M.","family":"Engbers","sequence":"first","affiliation":[{"name":"Erasmus MC Cancer Institute, University Medical Center Rotterdam, Department of Molecular Genetics, Department of Radiology and Nuclear Medicine","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Nonnekens","sequence":"additional","affiliation":[{"name":"Erasmus MC Cancer Institute, University Medical Center Rotterdam, Department of Molecular Genetics, Department of Radiology and Nuclear Medicine","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Sabatella","sequence":"additional","affiliation":[{"name":"Erasmus MC Cancer Institute, University Medical Center Rotterdam, Department of Molecular Genetics, Department of Radiology and Nuclear Medicine","place":["Rotterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-025-01069-z","article-title":"The molecular blueprint of targeted radionuclide therapy","volume":"22","author":"Primac","year":"2025","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1607427","article-title":"Phase 3 trial of (177)Lu-dotatate for midgut neuroendocrine tumors","volume":"376","author":"Strosberg","year":"2017","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2107322","article-title":"Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer","volume":"385","author":"Sartor","year":"2021","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s00259-014-2893-5","article-title":"Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors","volume":"42","author":"Bodei","year":"2015","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2015.00012","article-title":"Introduction to radiobiology of targeted radionuclide therapy","volume":"2","author":"Pouget","year":"2015","journal-title":"Front Med (Lausanne)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/rpd\/ncl495","article-title":"Radiation-induced DNA damage responses","volume":"122","author":"Jeggo","year":"2006","journal-title":"Radiat Prot Dosimetry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.nucmedbio.2021.11.005","article-title":"From the target cell theory to a more integrated view of radiobiology in targeted radionuclide therapy: the Montpellier group's experience","author":"Pouget","year":"2022","journal-title":"Nucl Med Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-019-04334-3","article-title":"Call to arms: need for radiobiology in molecular radionuclide therapy","volume":"46","author":"Terry","year":"2019","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2022.04.008","article-title":"Status of radiobiology in molecular radionuclide therapy - hope for the future","author":"Nonnekens","year":"2022","journal-title":"Nucl Med Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2020.07.002","article-title":"The radiobiology of radiopharmaceuticals","volume":"31","author":"Morris","year":"2021","journal-title":"Semin Radiat Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"102","DOI":"10.3390\/ijms17010102","article-title":"Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization","volume":"17","author":"Maier","year":"2016","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"591","DOI":"10.3390\/ph19040591","article-title":"Radiation biology of radiopharmaceuticals: beyond external beam radiation therapy","volume":"19","author":"Olson","year":"2026","journal-title":"Pharm (Basel)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1667\/rade-24-00024.1","article-title":"Dose rate effects from the 1950s through to the era of FLASH","volume":"202","author":"Held","year":"2024","journal-title":"Radiat Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1259\/bjr.20180070","article-title":"Radiation repair models for clinical application","volume":"92","author":"Dale","year":"2019","journal-title":"Br J Radiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1088\/0031-9155\/41\/10\/001","article-title":"Dose-rate effects in targeted radiotherapy","volume":"41","author":"Dale","year":"1996","journal-title":"Phys Med Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/s40658-018-0217-8","article-title":"Comparison of radiobiological parameters for (90)Y radionuclide therapy (RNT) and external beam radiotherapy (EBRT) in vitro","volume":"5","author":"Gholami","year":"2018","journal-title":"EJNMMI Phys"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.105.028183","article-title":"MIRD continuing education: bystander and low dose-rate effects: are these relevant to radionuclide therapy","volume":"48","author":"Sgouros","year":"2007","journal-title":"J Nucl Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.125.269470","article-title":"Establishing in vitro dosimetric models and dose-effect relationships for (177)Lu-DOTATATE in neuroendocrine tumors","volume":"66","author":"Tamborino","year":"2025","journal-title":"J Nucl Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14010235","article-title":"Hyperfractionated treatment with (177)Lu-octreotate increases tumor response in human small-intestine neuroendocrine GOT1 tumor model","volume":"14","author":"Elvborn","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1667\/rr14766.1","article-title":"Cellular response to exponentially increasing and decreasing dose rates: implications for treatment planning in targeted radionuclide therapy","volume":"188","author":"Solanki","year":"2017","journal-title":"Radiat Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1667\/rr0640.1","article-title":"Adaptive responses to low-dose\/low-dose-rate gamma rays in normal human fibroblasts: the role of growth architecture and oxidative metabolism","volume":"166","author":"de Toledo","year":"2006","journal-title":"Radiat Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/0360-3016(90)90467-x","article-title":"Radiobiological aspects of low dose rates in radioimmunotherapy","volume":"18","author":"Fowler","year":"1990","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1667\/RR0668.1","article-title":"Relative biological effectiveness of the alpha-particle emitter (211)At for double-strand break induction in human fibroblasts","volume":"167","author":"Claesson","year":"2007","journal-title":"Radiat Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181473","article-title":"In vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy","volume":"12","author":"Chan","year":"2017","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2005.20.52","article-title":"A comparison of high- versus low-linear energy transfer somatostatin receptor targeted radionuclide therapy in vitro","volume":"20","author":"Nayak","year":"2005","journal-title":"Cancer Biother Radiopharm"},{"key":"B26","doi-asserted-by":"publisher","first-page":"6602","DOI":"10.3390\/ijms21186602","article-title":"Comparison of high- and low-LET radiation-induced DNA double-strand break processing in living cells","volume":"21","author":"Roobol","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-022-05821-w","article-title":"In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T","volume":"49","author":"Ruigrok","year":"2022","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B28","doi-asserted-by":"publisher","first-page":"12369","DOI":"10.3390\/ijms232012369","article-title":"Understanding the radiobiological mechanisms induced by (177)Lu-DOTATATE in comparison to external beam radiation therapy","volume":"23","author":"Delbart","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41392-024-02080-z","article-title":"Cyclin-dependent protein kinases and cell cycle regulation in biology and disease","volume":"10","author":"Pellarin","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.2.7550","article-title":"p21Cip1\/WAF1 mediates cyclin B1 degradation in response to DNA damage","volume":"8","author":"Gillis","year":"2009","journal-title":"Cell Cycle"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/170325","article-title":"New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy","volume":"2012","author":"Mirzayans","year":"2012","journal-title":"J BioMed Biotechnol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210516","article-title":"p21(Waf1\/Cip1\/Sdi1) mediates retinoblastoma protein degradation","volume":"26","author":"Broude","year":"2007","journal-title":"Oncogene"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/s1535-6108(03)00048-5","article-title":"Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A","volume":"3","author":"S\u00f8rensen","year":"2003","journal-title":"Cancer Cell"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s004410000188","article-title":"Radiation-induced apoptosis","volume":"301","author":"Verheij","year":"2000","journal-title":"Cell Tissue Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.19.3.2109","article-title":"Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts","volume":"19","author":"Stein","year":"1999","journal-title":"Mol Cell Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/jci95148","article-title":"Mechanisms and functions of cellular senescence","volume":"128","author":"Herranz","year":"2018","journal-title":"J Clin Invest"},{"key":"B37","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/s41598-020-79934-3","article-title":"Radiation-induced cell cycle perturbations: a computational tool validated with flow-cytometry data","volume":"11","author":"Lonati","year":"2021","journal-title":"Sci Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7150\/thno.15311","article-title":"Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib","volume":"6","author":"Nonnekens","year":"2016","journal-title":"Theranostics"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.22.4.1049-1059.2002","article-title":"Two molecularly distinct G(2)\/M checkpoints are induced by ionizing irradiation","volume":"22","author":"Xu","year":"2002","journal-title":"Mol Cell Biol"},{"key":"B40","article-title":"Participation of p53 protein in the cellular response to DNA damage","volume":"51","author":"Kastan","year":"1991","journal-title":"Cancer Res"},{"key":"B41","article-title":"G2\/M checkpoint is p53-dependent and independent after irradiation in five human sarcoma cell lines","volume":"19","author":"Bache","year":"1999","journal-title":"Anticancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5393.1497","article-title":"Requirement for p53 and p21 to sustain G2 arrest after DNA damage","volume":"282","author":"Bunz","year":"1998","journal-title":"Science"},{"key":"B43","article-title":"Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents","volume":"46","author":"Fingert","year":"1986","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0006-3495(65)86700-5","article-title":"X-ray and ultraviolet sensitivity of synchronized Chinese hamster cells at various stages of the cell cycle","volume":"5","author":"Sinclair","year":"1965","journal-title":"Biophys J"},{"key":"B45","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/s0006-3495(63)86801-0","article-title":"Variations in several responses of HeLa cells to x-irradiation during the division cycle","volume":"3","author":"Terasima","year":"1963","journal-title":"Biophys J"},{"key":"B46","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13008-024-00116-y","article-title":"Cancer radioresistance is characterized by a differential lipid droplet content along the cell cycle","volume":"19","author":"Pagliari","year":"2024","journal-title":"Cell Div"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2004.03.005","article-title":"Role of cell cycle in mediating sensitivity to radiotherapy","volume":"59","author":"Pawlik","year":"2004","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3109\/09553002.2011.538127","article-title":"RBE of \u03b1-particles from (211)At for complex DNA damage and cell survival in relation to cell cycle position","volume":"87","author":"Claesson","year":"2011","journal-title":"Int J Radiat Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-1004-0021","article-title":"Mechanisms of cell sensitization to alpha radioimmunotherapy by doxorubicin or paclitaxel in multiple myeloma cell lines","volume":"11","author":"Supiot","year":"2005","journal-title":"Clin Cancer Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0677-4","article-title":"The therapeutic effectiveness of (177)Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2\/M cell cycle arrest","volume":"34","author":"Pichard","year":"2020","journal-title":"Leukemia"},{"key":"B51","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1186\/s12885-018-4836-1","article-title":"Combination of lutetium-177 labelled anti-L1CAM antibody chCE7 with the clinically relevant protein kinase inhibitor MK1775: a novel combination against human ovarian carcinoma","volume":"18","author":"Lindenblatt","year":"2018","journal-title":"BMC Cancer"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2013.06.007","article-title":"Biological consequences of radiation-induced DNA damage: relevance to radiotherapy","volume":"25","author":"Lomax","year":"2013","journal-title":"Clin Oncol (R Coll Radiol)"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.3390\/pharmaceutics15122761","article-title":"DNA damage by radiopharmaceuticals and mechanisms of cellular repair","volume":"15","author":"Khazaei Monfared","year":"2023","journal-title":"Pharmaceutics"},{"key":"B54","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.3390\/cancers12082098","article-title":"DNA damage-inducing anticancer therapies: from global to precision damage","volume":"12","author":"Reuvers","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.910440","article-title":"Chromatin and the cellular response to particle radiation-induced oxidative and clustered DNA damage","volume":"10","author":"Danforth","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1042\/ebc20200013","article-title":"Base excision repair and its implications to cancer therapy","volume":"64","author":"Grundy","year":"2020","journal-title":"Essays Biochem"},{"key":"B57","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1093\/mutage\/15.4.289","article-title":"Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations","volume":"15","author":"Pfeiffer","year":"2000","journal-title":"Mutagenesis"},{"key":"B58","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/s41580-019-0152-0","article-title":"DNA double-strand break repair-pathway choice in somatic mammalian cells","volume":"20","author":"Scully","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1667\/rr3489.1","article-title":"Repair of DNA damage induced by accelerated heavy ions in mammalian cells proficient and deficient in the non-homologous end-joining pathway","volume":"165","author":"Okayasu","year":"2006","journal-title":"Radiat Res"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.tm117.000375","article-title":"Repair of DNA double-strand breaks by mammalian alternative end-joining pathways","volume":"293","author":"Sallmyr","year":"2018","journal-title":"J Biol Chem"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01009","article-title":"Altering DNA repair to improve radiation therapy: specific and multiple pathway targeting","volume":"9","author":"Biau","year":"2019","journal-title":"Front Oncol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.120.248062","article-title":"Combination strategies to improve targeted radionuclide therapy","volume":"61","author":"Chan","year":"2020","journal-title":"J Nucl Med"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.7150\/thno.82963","article-title":"DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo","volume":"13","author":"Reuvers","year":"2023","journal-title":"Theranostics"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.7150\/thno.84628","article-title":"A genome-wide CRISPR\/Cas9 screen identifies DNA-PK as a sensitiser to (177)Lutetium-DOTA-octreotate radionuclide therapy","volume":"13","author":"Waldeck","year":"2023","journal-title":"Theranostics"},{"key":"B65","doi-asserted-by":"publisher","first-page":"915","DOI":"10.3390\/cancers15030915","article-title":"In vivo efficacy testing of peptide receptor radionuclide therapy radiosensitization using olaparib","volume":"15","author":"Feijtel","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B66","doi-asserted-by":"publisher","first-page":"10196","DOI":"10.1038\/s41598-020-67199-9","article-title":"Enhancing the anti-tumour activity of (177)Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP","volume":"10","author":"Cullinane","year":"2020","journal-title":"Sci Rep"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3724\/abbs.2022153","article-title":"Triple kill: DDR inhibitors, radiotherapy and immunotherapy leave cancer cells with no escape","volume":"54","author":"Qiu","year":"2022","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B68","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/s1367-5931(99)80014-3","article-title":"How does radiation kill cells","volume":"3","author":"Jonathan","year":"1999","journal-title":"Curr Opin Chem Biol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207528","article-title":"Cell death by mitotic catastrophe: a molecular definition","volume":"23","author":"Castedo","year":"2004","journal-title":"Oncogene"},{"key":"B70","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: a review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol Pathol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.172","article-title":"The clearance of dying cells: table for two","volume":"23","author":"Green","year":"2016","journal-title":"Cell Death Differ"},{"key":"B72","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjz010","article-title":"Understanding p53 functions through p53 antibodies","volume":"11","author":"Sabapathy","year":"2019","journal-title":"J Mol Cell Biol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80434-1","article-title":"Cytochrome c and dATP-dependent formation of Apaf-1\/caspase-9 complex initiates an apoptotic protease cascade","volume":"91","author":"Li","year":"1997","journal-title":"Cell"},{"key":"B75","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.det.2007.06.010","article-title":"Death receptors and apoptosis","volume":"25","author":"Contassot","year":"2007","journal-title":"Dermatol Clin"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008672","article-title":"Cellular mechanisms controlling caspase activation and function","volume":"5","author":"Parrish","year":"2013","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.7150\/thno.82101","article-title":"Imaging DNA damage response by \u03b3H2AX in vivo predicts treatment response to Lutetium-177 radioligand therapy and suggests senescence as a therapeutically desirable outcome","volume":"13","author":"O'Neill","year":"2023","journal-title":"Theranostics"},{"key":"B78","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s13550-019-0500-2","article-title":"Transcriptional effects of (177)Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice","volume":"9","author":"Spetz","year":"2019","journal-title":"EJNMMI Res"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2018.01.006","article-title":"Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after (177)Lu[Lu]-octreotate therapy","volume":"60","author":"Spetz","year":"2018","journal-title":"Nucl Med Biol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1186\/s13550-016-0247-y","article-title":"Priming increases the anti-tumor effect and therapeutic window of (177)Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1","volume":"7","author":"Dalmo","year":"2017","journal-title":"EJNMMI Res"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.apradiso.2017.04.016","article-title":"Assessment of cell death mechanisms triggered by (177)Lu-anti-CD20 in lymphoma cells","volume":"138","author":"Azor\u00edn-Vega","year":"2018","journal-title":"Appl Radiat Isot"},{"key":"B82","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.3390\/biom11111695","article-title":"p53-mediated radiosensitization of (177)Lu-DOTATATE in neuroblastoma tumor spheroids","volume":"11","author":"Lundsten","year":"2021","journal-title":"Biomolecules"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25607","article-title":"An evaluation in vitro of the efficacy of nutlin-3 and topotecan in combination with (177)Lu-DOTATATE for the treatment of neuroblastoma","volume":"9","author":"Tesson","year":"2018","journal-title":"Oncotarget"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-003-1216-z","article-title":"Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells","volume":"30","author":"Friesen","year":"2003","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-18-3295","article-title":"Drugs that modify cholesterol metabolism alter the p38\/JNK-mediated targeted and nontargeted response to alpha and Auger radioimmunotherapy","volume":"25","author":"Ladjohounlou","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2015.6309","article-title":"Localized irradiation of cell membrane by Auger electrons is cytotoxic through oxidative stress-mediated nontargeted effects","volume":"25","author":"Paillas","year":"2016","journal-title":"Antioxid Redox Signal"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.mcr-07-0100","article-title":"(Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1","volume":"5","author":"Min","year":"2007","journal-title":"Mol Cancer Res"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.mct-06-0558","article-title":"Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas","volume":"6","author":"Senkal","year":"2007","journal-title":"Mol Cancer Ther"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m610157200","article-title":"Alterations of ceramide\/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells","volume":"282","author":"Baran","year":"2007","journal-title":"J Biol Chem"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.056523","article-title":"Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms","volume":"76","author":"Walker","year":"2009","journal-title":"Mol Pharmacol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439245","article-title":"Senescence and apoptosis: dueling or complementary cell fates","volume":"15","author":"Childs","year":"2014","journal-title":"EMBO Rep"},{"key":"B92","doi-asserted-by":"publisher","first-page":"13173","DOI":"10.3390\/ijms222313173","article-title":"Mechanisms and regulation of cellular senescence","volume":"22","author":"Roger","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155725","article-title":"Both complexity and location of DNA damage contribute to cellular senescence induced by ionizing radiation","volume":"11","author":"Zhang","year":"2016","journal-title":"PLoS One"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-016-4065-0","article-title":"The cell fate: senescence or quiescence","volume":"43","author":"Terzi","year":"2016","journal-title":"Mol Biol Rep"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.130683","article-title":"The implications of radiotherapy-induced cellular senescence for cancer treatment and tumor microenvironment modulation","volume":"22","author":"Jiang","year":"2026","journal-title":"Int J Biol Sci"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2019.02.003","article-title":"Radiotherapy-induced senescence and its effects on responses to treatment","volume":"31","author":"Tabasso","year":"2019","journal-title":"Clin Oncol (R Coll Radiol)"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m111.250357","article-title":"Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21","volume":"287","author":"Masgras","year":"2012","journal-title":"J Biol Chem"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-16-0690","article-title":"BTK modulates p53 activity to enhance apoptotic and senescent responses","volume":"76","author":"Althubiti","year":"2016","journal-title":"Cancer Res"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27316","article-title":"Cellular senescence and tumor suppressor gene p16","volume":"130","author":"Rayess","year":"2012","journal-title":"Int J Cancer"},{"key":"B100","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.3390\/cells12081209","article-title":"Residual foci of DNA damage response proteins in relation to cellular senescence and autophagy in X-ray irradiated fibroblasts","volume":"12","author":"Osipov","year":"2023","journal-title":"Cells"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0265281","article-title":"A systems radiation biology approach to unravel the role of chronic low-dose-rate gamma-irradiation in inducing premature senescence in endothelial cells","volume":"17","author":"Babini","year":"2022","journal-title":"PLoS One"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1007\/s00412-018-0659-8","article-title":"Ki-67: more than a proliferation marker","volume":"127","author":"Sun","year":"2018","journal-title":"Chromosoma"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.7150\/thno.31179","article-title":"Preclinical efficacy of hK2 targeted [(177)Lu]hu11B6 for prostate cancer theranostics","volume":"9","author":"Timmermand","year":"2019","journal-title":"Theranostics"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.05.015","article-title":"Senescence in cancer","volume":"43","author":"Colucci","year":"2025","journal-title":"Cancer Cell"},{"key":"B105","doi-asserted-by":"publisher","first-page":"100960","DOI":"10.1016\/j.xcrm.2025.101945","article-title":"A (211)At-labelled mGluR1 inhibitor induces cancer senescence to elicit long-lasting anti-tumor efficacy","volume":"4","author":"Xie","year":"2023","journal-title":"Cell Rep Med"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1186\/2041-9414-1-13","article-title":"Emerging role of radiation induced bystander effects: Cell communications and carcinogenesis","volume":"1","author":"Baskar","year":"2010","journal-title":"Genome Integr"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11137","article-title":"Cell death: a review of the major forms of apoptosis, necrosis and autophagy","volume":"43","author":"D'Arcy","year":"2019","journal-title":"Cell Biol Int"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.2176\/nmc.ra.2014-0188","article-title":"Pathophysiology, diagnosis, and treatment of radiation necrosis in the brain","volume":"55","author":"Miyatake","year":"2015","journal-title":"Neurol Med Chir (Tokyo)"},{"key":"B109","doi-asserted-by":"publisher","first-page":"6968","DOI":"10.3390\/ijms26146968","article-title":"Effects of targeted radionuclide therapy on cancer cells beyond the ablative radiation dose","volume":"26","author":"Ferro-Flores","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1007\/s11307-025-02013-4","article-title":"Targeted radionuclide therapy using a lutetium-177 labeled human anti-CD133 antibody","volume":"27","author":"Wyszatko","year":"2025","journal-title":"Mol Imaging Biol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16868","article-title":"Radioimmunotherapy for CD133(+) colonic cancer stem cells inhibits tumor development in nude mice","volume":"8","author":"Weng","year":"2017","journal-title":"Oncotarget"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-08-0797","article-title":"Integrin alphavbeta3-targeted radioimmunotherapy of glioblastoma multiforme","volume":"14","author":"Veeravagu","year":"2008","journal-title":"Clin Cancer Res"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.mct-07-0132","article-title":"213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe","volume":"6","author":"Seidl","year":"2007","journal-title":"Mol Cancer Ther"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.031","article-title":"Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase","volume":"148","author":"Sun","year":"2012","journal-title":"Cell"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1038\/nature14191","article-title":"Necroptosis and its role in inflammation","volume":"517","author":"Pasparakis","year":"2015","journal-title":"Nature"},{"key":"B116","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1186\/s13046-019-1423-5","article-title":"Necroptosis regulates tumor repopulation after radiotherapy via RIP1\/RIP3\/MLKL\/JNK\/IL8 pathway","volume":"38","author":"Wang","year":"2019","journal-title":"J Exp Clin Cancer Res"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf6290","article-title":"ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation","volume":"7","author":"Yang","year":"2021","journal-title":"Sci Adv"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-4621-6","article-title":"RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma","volume":"37","author":"Das","year":"2016","journal-title":"Tumour Biol"},{"key":"B119","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1186\/s13014-022-02171-7","article-title":"Radiotherapy modulates tumor cell fate decisions: a review","volume":"17","author":"Chen","year":"2022","journal-title":"Radiat Oncol"},{"key":"B120","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-019-0263-3","article-title":"The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression","volume":"30","author":"Lei","year":"2020","journal-title":"Cell Res"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.202","article-title":"FAP-targeted radionuclide therapy induces ferroptosis in cancer-associated fibroblasts via disrupting iron homeostasis and redox balance","author":"Li","year":"2025","journal-title":"Acta Pharm Sin B"},{"key":"B123","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s12967-024-04958-6","article-title":"Autophagy inhibition improves the targeted radionuclide therapy efficacy of (131)I-FAP-2286 in pancreatic cancer xenografts","volume":"22","author":"Liu","year":"2024","journal-title":"J Transl Med"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2015.00074","article-title":"Alpha particles induce autophagy in multiple myeloma cells","volume":"2","author":"Gorin","year":"2015","journal-title":"Front Med (Lausanne)"},{"key":"B125","doi-asserted-by":"publisher","first-page":"678","DOI":"10.3390\/cancers13040678","article-title":"Enhance the immune checkpoint inhibitors efficacy with radiotherapy induced immunogenic cell death: A comprehensive review and latest developments","volume":"13","author":"Procureur","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.03.040","article-title":"The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling","volume":"54","author":"Cai","year":"2014","journal-title":"Mol Cell"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-21-4332","article-title":"Combining targeted radionuclide therapy and immune checkpoint inhibition for cancer treatment","volume":"28","author":"Kleinendorst","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1719","article-title":"Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing","volume":"5","author":"Gameiro","year":"2014","journal-title":"Oncotarget"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-023-03379-6","article-title":"Radiotherapy enhances CXCR3(high)CD8(+) T cell activation through inducing IFN\u03b3-mediated CXCL10 and ICAM-1 expression in lung cancer cells","volume":"72","author":"Wang","year":"2023","journal-title":"Cancer Immunol Immunother"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02606-8","article-title":"Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy","volume":"69","author":"Rouanet","year":"2020","journal-title":"Cancer Immunol Immunother"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-18-3476","article-title":"Mesothelin-targeted thorium-227 conjugate (MSLN-TTC): preclinical evaluation of a new targeted alpha therapy for mesothelin-positive cancers","volume":"25","author":"Hagemann","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.7150\/thno.54881","article-title":"Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy","volume":"11","author":"Jagodinsky","year":"2021","journal-title":"Theranostics"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002387","article-title":"Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy","volume":"9","author":"Lejeune","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.7150\/thno.45540","article-title":"PET imaging facilitates antibody screening for synergistic radioimmunotherapy with a (177)Lu-labeled \u03b1PD-L1 antibody","volume":"11","author":"Ren","year":"2021","journal-title":"Theranostics"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics3040344","article-title":"Induction of anti-tumor immune responses by peptide receptor radionuclide therapy with (177)Lu-DOTATATE in a murine model of a human neuroendocrine tumor","volume":"3","author":"Wu","year":"2013","journal-title":"Diagnostics (Basel)"},{"key":"B136","doi-asserted-by":"publisher","first-page":"4843","DOI":"10.3390\/ijms22094843","article-title":"Combined radionuclide therapy and immunotherapy for treatment of triple negative breast cancer","volume":"22","author":"Vito","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B137","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s42003-019-0327-4","article-title":"(90)Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell Non-Hodgkin's Lymphoma","volume":"2","author":"Hernandez","year":"2019","journal-title":"Commun Biol"},{"key":"B138","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2025.06.3855","article-title":"Evaluating the immune response after targeted radionuclide therapy: toward a correlation between absorbed dose and response","author":"Perrin","year":"2025","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.7150\/thno.39203","article-title":"Integrin \u03b1(v)\u03b2(3)-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy","volume":"9","author":"Chen","year":"2019","journal-title":"Theranostics"},{"key":"B140","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-20-4790","article-title":"Radium-223 treatment increases immune checkpoint expression in extracellular vesicles from the metastatic prostate cancer bone microenvironment","volume":"27","author":"Vardaki","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B141","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-025-07152-y","article-title":"Recommendations for reporting preclinical radiobiological studies in targeted radionuclide therapy","volume":"52","author":"Mendes","year":"2025","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B142","doi-asserted-by":"publisher","DOI":"10.1007\/s13139-026-00988-8","article-title":"Personalised dosimetry in nuclear medicine: bridging physics, biology and AI for next generation radiopharmaceutical therapy","author":"Shanmugiah","year":"2026","journal-title":"Nucl Med Mol Imaging"},{"key":"B143","doi-asserted-by":"publisher","DOI":"10.1118\/1.3615164","article-title":"3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs","volume":"38","author":"Lagerl\u00f6f","year":"2011","journal-title":"Med Phys"},{"key":"B144","doi-asserted-by":"publisher","DOI":"10.1080\/09553002.2021.1913529","article-title":"Expanding roles of cell cycle checkpoint inhibitors in radiation oncology","volume":"99","author":"Hauge","year":"2023","journal-title":"Int J Radiat Biol"},{"key":"B145","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb3631","article-title":"Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade","volume":"13","author":"Patel","year":"2021","journal-title":"Sci Transl Med"},{"key":"B146","volume-title":"Radiobiology for the Radiologist","author":"Hall","year":"2019"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1880443\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:23:06Z","timestamp":1784262186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1880443\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":146,"alternative-id":["10.3389\/fonc.2026.1880443"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1880443","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"article-number":"1880443"}}