Microenvironmental remodeling in FLASH radiotherapy

FLASH radiotherapy (FLASH-RT), characterized by ultra-high dose rate irradiation (>40 Gy/s), has emerged as a promising strategy for expanding the therapeutic window by sparing normal tissues while preserving tumor control. This review proposes a microenvironment-centered framework that interprets FLASH-RT as a physical-chemical-biological continuum: beam parameters and energy deposition shape oxygen dynamics and radical chemistry, which subsequently influence cellular stress responses, tissue repair, immune regulation, and late remodeling. Within this framework, we integrate current evidence regarding physical prerequisites, organ-specific normal-tissue responses, tumor-control outcomes, early clinical translation, and biological mechanisms. Preclinical studies across the central nervous system, lung, gastrointestinal tract, skin, and other organ systems suggest that FLASH-RT can attenuate acute inflammation, preserve stem and progenitor cell populations and regenerative capacity, reduce persistent DNA damage and cellular senescence, and mitigate late fibrosis. In several tumor models, FLASH-RT has maintained tumor control comparable to that achieved with conventional dose rate radiotherapy, without clear evidence of compromised antitumor efficacy. Early clinical studies have demonstrated feasibility and preliminary safety in superficial skin lesions and palliative treatment of bone metastases. Mechanistically, FLASH-induced microenvironmental remodeling may involve altered oxygen dynamics and radical chemistry, attenuation of inflammatory and fibrotic signaling, preservation of mitochondrial homeostasis, and modulation of immune responses. However, these responses are not uniform and depend on radiation modality, linear energy transfer, dose-rate structure, tissue context, and postirradiation time. By linking upstream irradiation conditions to downstream microenvironmental remodeling, this framework clarifies both shared responses and beam- or context-specific mechanisms. Standardized dosimetry, dynamic in vivo measurements, and paired tumor-normal tissue evaluations remain essential for testing causal relationships and guiding clinical translation.