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Review
. 2024 May 14;13(10):835.
doi: 10.3390/cells13100835.

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 , Harry E Ruda  3   4
Affiliations
Review

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

James C L Chow et al. Cells. .

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; biological process; cancer cell kill; cell function; normal cell sparing; oxygen depletion; physicochemical process; preclinical model; radiotherapy; ultra-high dose rate.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic diagram showing the primary physicochemical and biological reactions subsequent to cellular and tissue exposure to radiation. CONV-RT disturbs both chemical and biological reactions, whereas FLASH-RT circumvents engagement with biochemical pathways, allowing it to bypass these reactions.
Figure 2
Figure 2
Schematic diagram showing the microenvironment when cancer cells have infiltrated the healthy tissue containing normal cells at the tumor margin.
Figure 3
Figure 3
Summary of physicochemical and biological processes in FLASH-RT over time following irradiation.
See this image and copyright information in PMC

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