FLASH Irradiation Modulates Immune Responses and Accelerates Lung Recovery: A Single‐Cell Perspective

Abstract Radiation therapy (RT) is essential for treating thoracic malignancies but often causes significant lung damage. FLASH‐RT, an ultra‐high dose rate irradiation technique, shows potential in reducing radiation‐induced lung injury (RILI) while maintaining tumor control. However, the underlying immune mechanisms remain poorly understood. This study investigates the immune and cellular responses to FLASH‐RT versus conventional dose rate (CONV) RT during the early phase of RILI. Using single‐cell RNA sequencing (scRNA‐seq), a dynamic landscape of the lung microenvironment is pictured during RILI within one‐week post‐irradiation. The analysis reveals that FLASH‐RT induces a more immediate but transient cellular response, while CONV‐RT causes sustained inflammation. FLASH irradiation significantly reduces neutrophil infiltration compared to CONV irradiation, particularly within the pro‐inflammatory Ccrl2 + subset. FLASH irradiation also triggers stronger activation of CD4 + CD40L + Th cells, which are critical for regulating immune responses and balancing inflammation. Moreover, FLASH irradiation attenuates pro‐inflammatory activation and intercellular signaling of Mefv⁺ monocytes, thereby restraining excessive macrophage‐driven inflammation. Additionally, FLASH irradiation enhances TGF‐β signaling and epithelial‐mesenchymal transition (EMT) in alveolar type 1 (AT1) cells, promoting tissue repair. These findings highlight FLASH‐RT's superior immune modulation and reparative potential, providing valuable insights into its clinical application for minimizing radiation damage and enhancing lung recovery.