S2526
Radiobiology – Immuno-radiobiology
ESTRO 2026
Conclusion: We demonstrate for the first time that MDR is a key physical parameter governing the skin-sparing effect of FLASH irradiation, with a strict threshold (>210 Gy/s) required for the consistent protection across biological endpoints. Furthermore, we uncover the novel "lysosomal membrane permeabilization - NLRP3 inflammasome activation" axis in macrophages as the essential mechanism underlying this MDR-dependent protection. This discovery of key physical and biological determinants thereby provides a foundational strategy to accelerate FLASH clinical translation. References: 1. Favaudon V, et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med. 2014;6:245ra93.2. Qi Z, et al. ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence. Autophagy. 2024;20:2000-16.3. Wei X, et al. Role of pyroptosis in inflammation and cancer. Cell Mol Immunol. 2022;19:971-92.4. Fu J, et al. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annu Rev Immunol. 2023;41:301- 16.5. Radulovic M, et al. Lysosomal membrane homeostasis and its importance in physiology and disease. Nat Rev Mol Cell Biol. 2025. Keywords: Skin injury, FLASH RT, Lysosomal membrane leakage Mini-Oral 2011 STING Activation Sustains CD8 ⁺ T-Cell Function via Fatty-Acid Oxidation Following Fractionated Radiotherapy Meidan Wang 1,2 , Liqun Wang 1 1 1. Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China. 2 2. Faculty of Biology, University of Freiburg, Freiburg, Germany Purpose/Objective: Fractionated radiotherapy (RT) induces direct tumor cell killing and activates innate immune pathways. Yet, the metabolic mechanisms underpinning sustained T- cell immunity post-RT remain incompletely understood. This study aimed to determine how tumor-intrinsic STING signaling reprograms CD8 ⁺ T-cell metabolism to facilitate durable antitumor immunity. Material/Methods: Syngeneic B16F10 and MC38 tumor models received either single-dose or fractionated RT (4 Gy × 3). Tumor- intrinsic STING dependency was assessed using Sting ⁻ / ⁻ variants. Type I interferon induction and tumor growth control were evaluated. Tumor-
Results: A MDR-dependent FLASH skin protective effect was observed in mice, which was sustained from the early to late post-irradiation phases. This effect was evident only when the MDR exceeded the threshold of 210 Gy/s and became more pronounced at higher dose rates. Cellular assays established the essential role of macrophages in this protective effect, a finding corroborated by in vivo studies where macrophage
depletion in mice completely abrogated the phenotype. Mechanistically, we found that
conventional irradiation triggered a damage cascade involving ROS generation, lysosomal membrane permeabilization, NLRP3 inflammasome activation, which ultimately led to pro-inflammatory polarization and cell death in macrophages. In contrast, FLASH-RT significantly attenuated initial ROS production, consequently limiting lysosomal membrane permeabilization, thereby inhibiting NLRP3 inflammasome activation and ultimately driving a protective anti-inflammatory macrophage phenotype. A series of perturbations confirmed this suppressed cascade, where each intervention—exogenous ROS, lysosomal membrane destabilization, or direct NLRP3 activation—completely abolished the FLASH protective effect.
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