立体定向体放射治疗(SBRT)在临床应用中，能够安全地向体内外的目标部位提供高剂量辐射。然而，每分治疗剂量的增高（低分疗法）使放射肿瘤学领域面临着新问题，尤其是关于放疗免疫调节效应的一系列剂量分数方案，这些方案可能会因不同的剂量-分数计划而发生改变。本文研究不同分数计划的免疫调节效应。我们在野生型C57BL/ 6J小鼠和STING缺陷小鼠模型中建立了皮下肿瘤模型，并比较了三种不同分数计划的肿瘤控制效果：2Gy ×8、4.5Gy ×3和10Gy × 1，这些计划在生物学有效剂量（BEDs）上相似。我们发现使用10Gy ×1的分数计划具有显着的抗肿瘤效果，这表明单剂高剂量能够诱导增强的抗肿瘤免疫力，与常规分数（2Gy ×8）和适度的低分疗法（4.5Gy ×3）相比。然而，在STING缺陷小鼠中，三种剂量-分数计划间的肿瘤控制差异并不显著，这表明cGAS/STING信号参与了单剂高剂量治疗方案的抗肿瘤免疫效应。从机制上来看，我们发现常规分数诱导细胞凋亡，相比之下，单高剂量更适合诱导坏死程序，导致由于细胞膜的破裂而释放的细胞内辐射诱导的双链DNA，然后在招募的巨噬细胞中激活dsDNA感知信号的cGAS/STING。此外，在单高剂量照射微环境中，一种名为iRhom2的抑制性菱形样假蛋白家族成员，在渗入的巨噬细胞中上调。因此，iRhom2积极调节STING并直接促进TNF-α分泌，加剧了治疗后肿瘤细胞的坏死程序，导致持续的dsDNA释放和cGAS/STING信号的抗肿瘤免疫力增强形成正反馈回路。iRhom2通过cGAS/STING信号和TNF驱动的细胞坏死程序放大抗肿瘤信号，并形成正反馈回路，随后实现了单剂高剂量辐射治疗。版权所有©2023 Elsevier Inc.

The clinical application of stereotactic body radiotherapy (SBRT) allows a high dose of radiation to be safely delivered to extracranial targets within the body; however, a high dose per fraction(hypofractionation) have opened up the radiation oncology field to new questions on a variety of dose-fractionation schedules, especially the immunomodulatory effects of radiotherapy, which can change following various dose-fractionation schedules. Herein we investigate the immunomodulatory effects of different fractionation schedules.We established subcutaneous tumor model in WT C57BL/6J mice and STING-deficient mice. And compared the tumor control efficacy of three different fractionation schedules: 2 Gy × 8, 4.5 Gy × 3, and 10 Gy × 1, which are similar biologically effective doses (BEDs).We found the fractionation schedule of 10 Gy × 1 had a significantly higher antitumor effect, suggesting that a single high dose induced enhanced antitumor immunity compared to conventional fractionation (2 Gy × 8) and moderate hypofractionation (4.5 Gy × 3). However, in STING-deficient mice, differential tumor control was not observed among the three dose-fractionation schedules, suggesting that cGAS/STING signaling is involved in the antitumor immune effects of single high-dose schedules. Mechanistically, we found that conventional fractionation induced apoptosis; by comparison, single high-dose was more attuned to induced necroptosis, leading to the release of intracellular irradiation-induced dsDNA due to the loss of plasma membrane integrity, which then activated the dsDNA sensing signaling cGAS/STING in the recruited macrophage. Furthermore, iRhom2, a member of the conserved family of inhibitory rhomboid-like pseudoproteases, was upregulated in infiltrated macrophages in the single high-dose irradiation microenvironment. Therefore, iRhom2 positively regulates STING and directly promotes TNF-α secretion, this exacerbates necroptosis of irradiated tumor cells, leading to continuous dsDNA release and enhancement of cGAS/STING signaling antitumor immunity in a positive feedback loop.iRhom2 amplifies antitumor signaling in a positive feedback loop mediated by cGAS/STING signaling and TNF-driven necroptosis following single high-dose radiation.Copyright © 2023. Published by Elsevier Inc.