Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti–CTLA-4 and its combination with anti–PD-1 rely on tumor cell–intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell–intrinsic RIG-I signaling induced caspase-3–mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103⁺ dendritic cells, subsequent expansion of tumor antigen–specific CD8⁺ T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5′– triphosphorylated RNA in both tumor and nonmalignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of DDX58 (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity, and prolonged overall survival. Moreover, in patients with melanoma treated with anti–CTLA-4 checkpoint blockade, high DDX58 RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor–mediated immunotherapy of cancer.

实现对免疫检查点抑制剂的持久临床反应仍然是一个挑战。在这里，我们证明了抗CTLA-4的免疫疗法及其与抗PD-1的组合依赖于胞浆RNA受体RIG-I的肿瘤细胞内在激活。从机制上讲，肿瘤细胞固有的RIG-1信号传导诱导caspase-3介导的肿瘤细胞死亡，CD103 ⁺树突状细胞交叉表达肿瘤相关抗原，随后肿瘤特异性抗原CD8 ⁺扩增。T细胞及其在肿瘤组织内的积累。一致地，在一些临床前癌症模型中，在肿瘤和非恶性宿主细胞中以5'–三磷酸化RNA靶向RIG-I的治疗靶点均有效增强了CTLA-4检查点阻断的功效。在人类中，对原发性黑色素瘤样品的转录组分析显示，DDX58（编码RIG-1的基因）的高表达，T细胞受体和抗原呈递途径的活性与延长的总生存期之间存在密切的联系。此外，在接受抗CTLA-4检查点封锁治疗的黑色素瘤患者中，高DDX58RIG-I转录活性与持久的临床反应显着相关。因此，我们的数据确定了RIG-I信号在肿瘤及其微环境中的激活是检查点抑制剂介导的癌症免疫治疗的重要组成部分。