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This review examines metabolic dependencies and cellular pathways that determine treatment response, including vulnerabilities in glucose, lipid, and amino-acid metabolism, and how these can be targeted to overcome resistance. It further discusses metabolic and molecular tumour profiling for therapy personalization and future directions such as metabolic imaging integration and systemic-combination strategies.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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Radiation: Undetectable Yet Deadly—A Review on Radiotherapy  \nFrancesco Fiorica 1, *, Umberto Tebano 1, Giuseppe Napoli 1, Antonella Franceschetto 1, Marco Muraro 1, Carlotta Giorgi 2 and Paolo Pinton 2  \nAcademic Editor: Brian Gabrielli  \nReceived: 27 November 2024  \nRevised: 18 December 2024  \nAccepted: 18 December 2024  \nPublished: 27 December 2024  \nCitation: Fiorica, F.; Tebano, U.; Napoli, G.; Franceschetto, A.; Muraro, M.; Giorgi, C.; Pinton, P.  \nMetabolic-Modulating Effects of Radiation: Undetectable Yet Deadly—AReview on Radiotherapy. Cancers 2025, 17, 54. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cancers17010054](10.3390/cancers17010054)  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37122 Verona, Italy; [umberto.tebano@auilss9.veneto.it](umberto.tebano@auilss9.veneto.it) (U.T.); [giuseppe.napoli@aulss9.veneto.it](giuseppe.napoli@aulss9.veneto.it) (G.N.); [antonella.franceschetto@aulss9.veneto.it](antonella.franceschetto@aulss9.veneto.it) (A.F.); [marco.muraro@aulss9.veneto.it](marco.muraro@aulss9.veneto.it) (M.M.)  \n2 Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 48033 Ferrara, Italy; [carlotta.giorgi@unife.it](carlotta.giorgi@unife.it) (C.G.); [paoilo.pinton@unife.it](paoilo.pinton@unife.it) (P.P.)  \n* [Correspondence: francesco.fiorica@aulss9.veneto.it](Correspondence: francesco.fiorica@aulss9.veneto.it)  \nSimple Summary: This review explores how radiotherapy disrupts critical metabolic pathways in cancer cells. It highlights vulnerabilities in glucose metabolism, lipid synthesis, and amino acid pathways, which radiotherapy exploits to enhance tumour control. Advancements such as nanoparticle-enhanced and FLASH radiotherapy are discussed for their ability to improve precision and reduce damage to healthy tissues. Tools like FDG-PETscans are emphasised for detecting metabolic changes and guiding therapy combinations, such as precision radiotherapy with metabolic inhibitors. This review also outlines future prospects, including personalised metabolic imaging, integration with systemic therapies, targeting tumour-specific metabolic dependencies, and innovations like immune modulation and ferroptosis induction. These approaches aim to transform radiotherapy from a localised treatment to a systemic strategy that targets cancer’s metabolic complexities, improving both efficacy and patient outcomes.  \nAbstract: Radiotherapy has traditionally been viewed as a localised treatment modality, primarily inducing DNA damage to eradicate cancer cells. However, emerging research reveals that radiation also profoundly affects cellular metabolism, particularly in reprogramming tumour cells’ energy production and survival pathways. This article explores the role of metabolic reprogramming in the response of cancer cells to radiotherapy, highlighting how these biological processes can be leveraged to enhance treatment efficacy and overcome resistance. Radiotherapy is also discussed, focusing on how metabolic and molecular profiling of tumours can help personalise radiation treatments to improve outcomes.  \nKeywords: Metabolic cancer pathway and radiotherapy; alternative radiation cell killing; radiation synergism  \n1. Introduction  \nFrom a cancer-centric perspective, radiotherapy has been primarily viewed as a localised treatment modality, targeting cancer tissues with ionising radiation to induce DNA damage and cell death [1]","cbCainN9CH48s92p","https://ap.wps.com/l/cbCainN9CH48s92p","pdf",868517,14,"English","# Introduction\n## Radiotherapy as DNA damage and cell death\n## Beyond direct DNA damage: metabolism and autophagy\n## Precision and emerging modalities\n## FLASH and nanoparticle-enhanced approaches","[{\"question\":\"How does radiotherapy affect cancer cells beyond DNA damage?\",\"answer\":\"Radiotherapy also profoundly alters cellular metabolism, reprogramming energy production and survival pathways that influence how tumours respond and develop resistance.\"},{\"question\":\"Which metabolic vulnerabilities does the review highlight for improving radiotherapy outcomes?\",\"answer\":\"The review emphasizes vulnerabilities across glucose metabolism, lipid synthesis, and amino-acid pathways that radiotherapy can exploit to enhance tumour control.\"},{\"question\":\"What technologies are discussed for detecting metabolic changes and guiding treatment?\",\"answer\":\"Metabolic imaging tools such as FDG-PET scans are emphasized for detecting metabolic shifts and supporting combination strategies, including precision radiotherapy with metabolic inhibitors.\"}]","Metabolic-Modulating Effects of Radiation: Undetectable Yet Deadly - A Review on Radiotherapy | PDF",1790000062,35]