Rosini Giulia, Ciarrocchi Esther, D'Orsi Beatrice
Institute of Neuroscience, Italian National Research Council, Pisa, Italy.
Department of Physics, University of Pisa, Pisa, Italy.
Front Cell Dev Biol. 2025 May 9;13:1575678. doi: 10.3389/fcell.2025.1575678. eCollection 2025.
Radiotherapy is a fundamental tool in cancer treatment, utilized in over 60% of cancer patients during their treatment course. While conventional radiotherapy is effective, it has limitations, including prolonged treatment durations, which extend patient discomfort, and toxicity to surrounding healthy tissues. FLASH radiotherapy (FLASH-RT), an innovative approach using ultra-high-dose-rate irradiation, has shown potential in selectively sparing normal tissues while maintaining unaltered tumor control. However, the precise mechanisms underlying this "FLASH effect" remain unclear. This mini-review explores key hypotheses, including oxygen depletion, radical-radical interactions, mitochondrial preservation, differential DNA damage repair, and immune modulation. Oxygen levels significantly affect tissue response to radiation by promoting radical recombination, preserving mitochondrial function, and differentially activating DNA repair pathways in normal versus tumor tissues. However, the extent to which oxygen depletion contributes to the FLASH effect remains debated. Additionally, FLASH-RT may modulate the immune response, reducing inflammation and preserving immune cell function. To further enhance its therapeutic potential, FLASH-RT is increasingly being combined with complementary strategies such as radioprotectors, immunomodulators, and nanotechnology platforms. These combinations aim to amplify tumor control while further reducing normal tissue toxicity, potentially overcoming current limitations. Despite promising preclinical evidence, the exact mechanisms and clinical applicability of FLASH-RT require further investigation. Addressing these gaps is crucial for optimizing FLASH-RT and translating its potential into improved therapeutic outcomes for cancer patients. Continued research is essential to harness the full benefits of the FLASH effect, offering a paradigm shift in radiation oncology.
放射治疗是癌症治疗的一项基本手段，超过60%的癌症患者在其治疗过程中会使用到。虽然传统放射治疗有效，但也存在局限性，包括治疗时间延长，这会增加患者的不适感，以及对周围健康组织产生毒性。FLASH放射治疗（FLASH-RT）是一种采用超高剂量率照射的创新方法，已显示出在选择性保护正常组织的同时保持肿瘤控制不变的潜力。然而，这种“FLASH效应”背后的确切机制仍不清楚。这篇小型综述探讨了关键假说，包括氧耗竭、自由基-自由基相互作用、线粒体保护、DNA损伤修复差异以及免疫调节。氧水平通过促进自由基重组、维持线粒体功能以及在正常组织与肿瘤组织中差异激活DNA修复途径，显著影响组织对辐射的反应。然而，氧耗竭对FLASH效应的贡献程度仍存在争议。此外，FLASH-RT可能会调节免疫反应，减轻炎症并维持免疫细胞功能。为了进一步提高其治疗潜力，FLASH-RT越来越多地与放射保护剂、免疫调节剂和纳米技术平台等互补策略相结合。这些组合旨在增强肿瘤控制，同时进一步降低正常组织毒性，有可能克服当前的局限性。尽管临床前证据很有前景，但FLASH-RT的确切机制和临床适用性仍需进一步研究。填补这些空白对于优化FLASH-RT并将其潜力转化为改善癌症患者的治疗效果至关重要。持续的研究对于充分利用FLASH效应的全部益处至关重要，这将为放射肿瘤学带来范式转变。
