Exploring radiation-induced fibrosis: biological mechanisms and new frontiers in research and therapeutics

Abstract

Purpose: Radiation-induced fibrosis (RIF) is a significant long-term complication of radiotherapy, affecting many cancer patients months to years after treatment. Characterized by progressive tissue stiffening, loss of elasticity, and impaired organ function, RIF can deleteriously impact a patient’s quality of life. Commonly affected sites include the skin, lung, heart, and kidney. Advances in radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), stereotactic body radiotherapy (SBRT), and image-guided radiotherapy (IGRT), have improved the precision of radiation delivery, reducing acute damage to healthy tissues; RIF however, remains a prevalent complication despite these technological advancements. This review explores the underlying cellular and molecular mechanisms of RIF, emphasizing fibroblast proliferation, myofibroblast activation, and excessive extracellular matrix (ECM) deposition in its progression. Additionally, this review highlights in vitro and in vivo models that are instrumental in studying RIF and evaluates current therapeutic strategies aimed at mitigating RIF. Conclusion: Radiation-induced fibrosis continues to affect a considerable number of patients due to the chronic nature of the fibrotic processes, driven by sustained fibroblast activation, ECM accumulation, and inflammatory responses. Newly developed approaches, such as stem cell-based therapies, TGF-β inhibitors, and molecular interventions aimed at ECM regulation, offer promising avenues for mitigating or reversing RIF. Additionally, integrating computational models into clinical practice could enhance personalized treatment planning, enabling better prediction and prevention of RIF in patients. Addressing these challenges is critical for improving the quality of life of patients affected by RIF and improving their outcomes, particularly with the growing population of long-term cancer survivors in the world.