Hui Luo, Chengliang Yang, Dan Hu, Kyle Vaugh Laster, Ronghu Mao, L. Ma, Hongchang Lei, H. Ge
Radiation-induced inflammatory responses are known to contribute to lung injury, but how these responses occur under ultra-high dose rate FLASH irradiation (FLASH) remains poorly characterized. The present study aimed to compare inflammation-mediated cancer progression in FLASH versus conventional (CONV) irradiation-induced lung injury in mice. Using a modified Varian 23CX clinical accelerator to deliver electron beam FLASH, we performed whole thoracic irradiation in healthy C57BL/6J mice with both FLASH and CONV modalities. While both triggered similar acute inflammatory responses, FLASH resulted in significantly less pulmonary fibrosis at 12 weeks post-irradiation. Acute radiation-induced lung inflammation promoted cancer progression in both groups, with neutrophil recruitment contributing to tumor cell metastasis. During chronic inflammation, however, FLASH led to fewer metastatic colonies than CONV. Further analysis revealed that FLASH accelerated macrophage polarization toward the M2 phenotype during chronic inflammation, whereas CONV promoted M1 polarization. Importantly, FLASH maintained tumor control comparable to CONV while markedly reducing normal tissue toxicity. These results demonstrate that radiation-induced inflammation facilitates cancer progression and suggest that differential macrophage polarization may help explain the distinct lung responses to CONV versus FLASH irradiation. Further studies are needed to elucidate the tissue changes that occur prior to tumor cell seeding in irradiated lungs.