Available online 30 December 2022

Radiation therapy has a fundamental role in the management of cancers. However, despite a constant improvement in radiotherapy techniques, the issue of radiation-induced side effects remains clinically relevant. Mechanisms of acute toxicity and late fibrosis are therefore important topics for translational research to improve the quality of life of patients treated with ionizing radiations. Tissue changes observed after radiotherapy are consequences of complex pathophysiology, involving macrophage activation, cytokine cascade, fibrotic changes, vascularization disorders, hypoxia, tissue destruction and subsequent chronic wound healing. Moreover, numerous data show the impact of these changes in the irradiated stroma on the oncogenic process, with interplays between tumor radiation response and pathways involved in the fibrotic process. The mechanisms of radiation-induced normal tissue inflammation are reviewed, with a focus on the impact of the inflammatory process on the onset of treatment-related toxicities and the oncogenic process. Possible targets for pharmacomodulation are also discussed.

Acute radiation-induced toxicities are classically defined as any toxicities observed in irradiated volumes and occurring within the first 3 to 6 months from radiation treatment. In the pathogenesis of radiation-induced symptoms, damages to the irradiated normal tissue, including epithelial cells and stromal cells (consisting of mesenchymal and connective tissue lineages) generate a strong inflammatory response (De Ruysscher et al., 2019). Radiation-induced symptoms increase in severity with

The onset of radiation-induced fibrosis is a major concern, as this process can worsen over time and lead to definitive functional impairment. Radiation-induced fibrosis results from an inappropriate regeneration process and usually occurs 6 to 12 months after radiotherapy exposure. It is basically a consequence of excessive production and deposition of extracellular matrix proteins, including collagenous. While normal healing requires the infiltration of immune cells into the injured area, the

The inflammatory process occurring after radiotherapy is complex and signaling pathways involved in the response to ionizing radiation remain only partially understood. Nevertheless, the analysis of the underlying biological mechanisms shows close interactions between sustained oxidative stress, macrophage activation, inflammatory cascade, hypoxia and fibrosis. In addition, many mechanisms involved into the acute and late response are common and the frontier between acute and late radiation

Tissue's inability to restore its homeostasis due to persisting inflammatory response is a characteristic of late fibrotic process, and this opens perspectives to restore pharmacologically a normal response in irradiated tissue, promoting normal healing rather than a fibrotic process (Chargari et al., 2020; Ejaz et al., 2019). The development of radiomitigators is however complex and requires sound translational research to ensure that the protection of healthy tissues is not accompanied by

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