放射疗法（RT）诱导DNA双链断裂，导致肿瘤细胞毒性和类型I 干扰素（IFN）通过干扰素基因激活剂（STING）激活的反应。我们研究了联合RT和共济失调毛细血管扩张抑制剂是否促进了这些效应并增强了肿瘤免疫。带有同种配型副肿瘤（MOC2头颈鳞状细胞癌或B78黑色素瘤）的小鼠接受了定向肿瘤RT和AZD0156口服治疗。使用特异性免疫细胞耗竭、类型1干扰素受体1基因敲除小鼠（IFNAR1-KO）和STING缺陷肿瘤细胞来研究RT和AZD0156治疗后肿瘤-免疫相互作用。与仅RT或AZD0156相比，联合RT和AZD0156减少了MOC2或B78肿瘤小鼠的肿瘤生长。低剂量的AZD0156（1-100 nM）单独不影响肿瘤细胞增殖，但与RT联合使用抑制了肿瘤细胞的集落形成能力。低剂量的AZD0156与RT协同增加了肿瘤细胞中的IFN-β、主要组织相容性复合物（MHC）-I和程序性死亡配体1（PD-L1）的表达。与野生型小鼠相反，IFNAR1-KO小鼠经RT+AZD0156治疗后表现出减少的CD8+T细胞肿瘤浸润和较差的生存率。CD8+T细胞耗竭减少了RT+AZD0156治疗期间的抗肿瘤反应。STING缺陷的MOC2（MOC2-STING+/-）或B78（B78-STING-/-）肿瘤消除了RT+AZD0156对IFN-β、MHC-I和PD-L1表达的影响，并减少了CD8+T细胞的浸润和迁移。额外的抗PD-L1治疗通过增加肿瘤-MHC-I和淋巴细胞活化促进了抗肿瘤反应。联合放射疗法和AZD0156增强了基于STING的抗肿瘤反应。源自肿瘤的细胞自主性IFN-β放大了肿瘤细胞表面的MHC-I和PD-L1诱导，这是抗PD-L1治疗在RT和AZD0156联合治疗后促进抗肿瘤免疫反应所需的。©作者（或其雇主）2023.根据CC BY-NC许可进行再次使用。不得进行商业再使用。由BMJ出版。

Radiation therapy (RT) elicits DNA double-strand breaks, resulting in tumor cytotoxicity and a type I interferon (IFN) response via stimulator of interferon genes (STING) activation. We investigated whether combining RT with an ataxia-telangiectasia mutated inhibitor promoted these effects and amplified tumor immunity.Mice-bearing syngeneic flank tumors (MOC2 head and neck squamous cell carcinoma or B78 melanoma) were treated with tumor-directed RT and oral administration of AZD0156. Specific immune cell depletion, type 1 interferon receptor 1 knock-out mice (IFNAR1-KO), and STING-deficient tumor cells were used to investigate tumor-immune crosstalk following RT and AZD0156 treatment.Combining RT and AZD0156 reduced tumor growth compared with RT or AZD0156 alone in mice bearing MOC2 or B78 tumors. Low-dose AZD0156 (1-100 nM) alone did not affect tumor cell proliferation but suppressed tumor cell clonogenicity in combination with RT. Low-dose AZD0156 with RT synergistically increased IFN-β, major histocompatibility complex (MHC)-I, and programmed death-ligand 1 (PD-L1) expression in tumor cells. In contrast to wild-type mice, IFNAR1-KO mice showed reduced CD8+T cell tumor infiltration and poor survival following RT+AZD0156 treatment. CD8+T cell depletion reduced antitumor response during RT+AZD0156 treatment. STING-deficient MOC2 (MOC2-STING+/-) or B78 (B78-STING-/-) tumors eliminated the effects of RT+AZD0156 on the expression of IFN-β, MHC-I, and PD-L1, and reduced CD8+T cell infiltration and migration. Additional anti-PD-L1 therapy promoted antitumor response by elevation of tumor-MHC-I and lymphocyte activation.Combined radiation and AZD0156 increase STING-dependent antitumor response. Tumor-derived cell-autonomous IFN-β amplification drives both MHC-I and PD-L1 induction at the tumor cell surface, which is required by anti-PD-L1 therapy to promote antitumor immune response following RT and AZD0156 combination therapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.