Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells

Sep 21, 2026

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The advent of FLASH radiotherapy (FLASH-RT) has driven a paradigm shift in cancer care, demonstrating strong normal-cell sparing at ultra-high dose rates (>40 Gy/s). This review explains the mechanisms behind the FLASH effect by integrating physicochemical and biological cell-biophysics hypotheses. Physicochemical contributions include oxygen depletion, reactive oxygen species, and free-radical recombination, while biological pathways involve immune modulation and effects on treatment-site blood vessels across multiple tissues. It evaluates selective cancer targeting and tumor microenvironment remodeling, discusses clinical integration implications and remaining knowledge gaps, and summarizes how combining these insights can guide future optimization for cancer therapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Overview of FLASH Radiotherapy (FLASH-RT)

FLASH effect and ultra-high dose rates

Historical development and key in vivo findings

cells Review Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells James C. L. Chow 1,2, * and Harry E. Ruda 3,4 Citation: Chow, J.C.L.; Ruda, H.E. Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells. Cells 2024, 13, 835 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells13100835 Received: 9 April 2024 Revised: 9 May 2024 Accepted: 11 May 2024 Published: 14 May 2024 Copyright: © 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://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1X6, Canada 2 Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada 3 Centre of Advance Nanotechnology, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada; [harry.ruda@utoronto.ca](harry.ruda@utoronto.ca) 4 Department of Materials Science and Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada * [Correspondence: james.chow@uhn.ca](Correspondence: james.chow@uhn.ca); Tel.: +1-416-946-4501 Abstract: The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s) . This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy. Keywords: FLASH; normal cell sparing; cancer cell kill; cell function; radiotherapy; ultra-high dose rate; preclinical model; oxygen depletion; biological process; physicochemical process 1. Introduction Radiotherapy (RT), extensively utilized in cancer treatment, utilizes high-energy ionizing radiation such as X-rays, electrons or protons to specifically target and disrupt cancer cell reproduction by inducing damage to its DNA. This approach inhibits the growth and division of cancer cells effectively [1–3] . While RT is a powerful method for treating various cancers, its drawback lies in potential damage to healthy cells, limiting the radiation dosage administered to tumors [4,5] . This constraint often results in incomplete tumor eradication and diminishes overall treatment efficacy [6] . To address these challenges, there is ongoing research to optimize RT outcomes based on cell radiobiology. Current techniques, such as stereotactic body RT [7] and intensity-

FAQs

What is FLASH radiotherapy (FLASH-RT) and what dose rate defines it?

FLASH-RT delivers radiation at ultra-high dose rates, typically greater than 40 Gy/s. Its defining feature is the FLASH effect that reduces damage to healthy cells while maintaining antitumor effectiveness.

Which physicochemical processes are proposed to drive the FLASH effect?

The review highlights oxygen depletion, reactive oxygen species, and free-radical recombination as major physicochemical contributors to the FLASH effect.

How does FLASH-RT influence biological systems beyond direct cancer-cell killing?

The biological mechanisms discussed include impacts on the immune system and modulation of blood vessels at treatment sites, which together can alter the tumor microenvironment and support therapeutic outcomes.

Sep 21, 2026

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