Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.

自噬支持细胞和生物体内的稳态。然而，对于癌症治疗是否应抑制或激活自噬尚不清楚。必需自噬基因的缺失增加了小鼠乳腺癌细胞对体外和体内放射免疫的敏感性（在具有免疫能力的同系宿主中）。自噬缺陷细胞分泌的I型干扰素（IFN）数量增加，这可能受到CGAS或STING抑制，线粒体DNA耗竭或通过BCL2过表达或BAX阻止线粒体外膜通透性的限制删除。在体内，受辐照的自噬能力不强的乳腺肿瘤可产生强大的免疫力，从而通过全身性I型IFN信号传导改善了对远距离未辐照病变的控制。最后，自噬的遗传特征在乳腺癌患者中具有负的预后价值，与线粒体丰度，I型干扰素信号传导和效应免疫力呈负相关。由于临床上有用的自噬抑制剂难以捉摸，我们的发现表明线粒体外膜通透性可能代表了增强乳腺癌患者放射治疗免疫原性的有效靶标。