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  • Perspective
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Mechanisms, challenges and opportunities for FLASH radiotherapy in cancer

Nature Reviews Cancer (2025)Cite this article

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Abstract

FLASH radiotherapy has the potential to improve both patient quality of life and outcomes by delivering radiation at ultrahigh dose rates to effectively target tumours while sparing healthy tissues. However, the differential sensitivity of healthy tissues versus tumours to FLASH radiotherapy remains unexplained. In this Perspective, we hypothesize that FLASH radiotherapy distinguishes healthy tissues from tumours based on subtle functional and structural biological differences. We identify commonalities present in the various healthy tissues that are spared by FLASH radiotherapy that might be lost during tumorigenesis. We also propose that a specific class of proteins, termed long-lived proteins, define a critical radiolytic target that are present in nearly every healthy tissue that is FLASH radiotherapy resistant yet are absent in tumours. We extend this structural hypothesis further by suggesting that tumour and extracellular matrix rigidity affects sensitivity to changes in radiotherapy dose rate, where more rigid and dense desmoplastic tumours are more sensitive to FLASH radiotherapy than those possessing more elasticity. Substantiating these concepts experimentally may provide a new and generalized mechanism of action of radiation effects and may therefore inform clinical trial designs by identifying those tumour subclasses expected to exhibit optimal responses to FLASH radiotherapy.

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Fig. 1: The relative timescale of measured radiation events involving physical, chemical and biological processes.
Fig. 2: The temporal and biological dynamics of radiation response.
Fig. 3: The differential toxicity effects induced by FLASH and conventional dose rate radiotherapy in healthy tissues and tumours.

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Acknowledgements

We would like to thank V. Favaudon (Inserm), M. Hetzer (ISTA), J. Lascaud (LMU), R. Abolfath (Howard U) and A. Durham (HUG) for fruitful scientific discussions as well as the junior fellows in our teams A. Almeida (Unige) and O. Drayson (UCI) for their support in preparing figures.

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Authors and Affiliations

  1. Radiation Oncology Department, Geneva University Hospital, Geneva, Switzerland

    Marie-Catherine Vozenin & Pelagia Tsoutsou

  2. Department of radiology and medical informatics, University of Geneva, Geneva, Switzerland

    Marie-Catherine Vozenin & Pelagia Tsoutsou

  3. Radiation Oncology department, Wilrijk, Belgium

    Pierre Montay-Gruel

  4. Antwerp Research in Radiation Oncology, University of Antwerp, Antwerp, Belgium

    Pierre Montay-Gruel

  5. Department of Radiation Oncology, University of California, Irvine, CA, USA

    Charles L. Limoli

Authors
  1. Marie-Catherine Vozenin
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  2. Pierre Montay-Gruel
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  4. Charles L. Limoli
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Marie-Catherine Vozenin.

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Competing interests

M.-C.V. declares one research grant from Varian, Siemens Healthineers dedicated to FLASH preclinical research, one research grant from IBA dedicated to FLASH preclinical research and one research grant from Roche dedicated to radio-immunotherapy. P.M.-G. and P.T. declare no competing interests. C.L.L. declares receiving consulting fees from IBA dedicated to FLASH developments.

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Glossary

Acoustic cavitation

The formation, growth and implosive collapse of bubbles in a liquid due to pressure fluctuations induced by sound waves, typically ultrasound.

Acoustic oscillation

The periodic variation in pressure, particle velocity and other acoustic quantities in a medium as a sound wave propagates through it.

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Extracellular matrix

A cellular stromal components composed of macromolecules (that is, proteins, carbohydrates and lipids) and minerals, which provide structural and biochemical support to cells.

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Free radical recombination

A chemical reaction in which two free radicals combine to form a stable, non-radical molecule.

Ionizing radiation

Particles or electromagnetic waves with sufficient energy to induce the ionization of atoms it interacts with, and in the context of external beam radiotherapy, these are often X-rays, protons, electrons or carbon ions.

Isodose

An equivalent dose given by two different irradiation modalities.

Proteostasis

The biological processes involved in the synthesis, folding, trafficking and degradation of proteins required for the proper maintenance of cellular functions.

Radiation chemistry

The study of the chemical effects and reactions induced by the absorption of ionizing radiation in matter.

Radiobiology

A branch of science studying the interactions of ionizing radiation with biological tissues and organisms.

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The consumption of oxygen by radiation-induced chemical reactions in aqueous systems, producing ROS and reducing overall oxygen level.

Radioresistance

Intrinsic or adaptive capacity of cells, tissues, organs or organisms to overcome the detrimental effects of ionizing radiation.

Therapeutic index

The measurement of treatment efficacy relative to its side effects.

Tumour clamping

An experimental procedure used to restrict blood flow to a tumour, inducing hypoxic or ischaemic conditions.

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Vozenin, MC., Montay-Gruel, P., Tsoutsou, P. et al. Mechanisms, challenges and opportunities for FLASH radiotherapy in cancer. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00878-9

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