Opportunities and Challenges in FLASH Radiotherapy: Focusing on Normal Tissue Protection Effects and Clinical Translation Bottleneck

ABSTRACT

FLASH radiotherapy (FLASH‐RT) has garnered significant attention for its “FLASH effect”, which selectively protects normal tissues while maintaining tumor‐killing efficacy at ultra‐high dose rates (UHDR). This technology represents a promising but still investigational therapeutic strategy in radiation oncology. Since the initial confirmation of the FLASH effect in mouse experiments in 2014, related research has rapidly advanced in key radiation physics parameters, radiation types, and biological mechanisms. However, a lack of consensus on its critical triggering conditions, tissue‐specific thresholds, and standardized parameters has hindered its transition from laboratory to clinical application. This review systematically outlines the physical triggering conditions of the FLASH effect, revealing its dependence on a multidimensional combination of parameters including dose rate, single‐fraction dose, pulse time structure, and radiation type. It also delves into the underlying multiscale biological mechanisms, encompassing radiochemical aspects such as transient oxygen depletion and free radical kinetics, cellular processes including DNA damage repair and cell death patterns, and systemic changes like immune microenvironment remodeling. It further examines three core challenges hindering FLASH‐RT's clinical implementation: technical feasibility and equipment limitations, the complexity and uncertainty of biological mechanisms, and challenges in clinical practice and standardization. This review aims to dissect current research progress and critical issues, providing guidance for advancing FLASH‐RT's clinical application.