Roulstone Victoria, Kyula-Currie Joan, Wright James, Patin Emmanuel C, Dean Isaac, Yu Lu, Barreiro-Alonso Aida, Melake Miriam, Choudhary Jyoti, Elliott Richard, Lord Christopher J, Mansfield David, Matthews Nik, Chauhan Ritika, Jennings Victoria, Chan Wah Hak Charleen, Baldock Holly, Butera Francesca, Appleton Elizabeth, Nenclares Pablo, Pederson Malin, Foo Shane, Wongariyapak Amarin, Rullan Antonio, Tenev Tencho, Meier Pascal, Vile Richard, Pandha Hardev, Melcher Alan, McLaughlin Martin, Harrington Kevin J
The Institute of Cancer Research, London, UK.
The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Nat Commun. 2025 May 25;16(1):4855. doi: 10.1038/s41467-025-60133-5.
Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.
双链RNA的细胞质模式识别受体（PRR），如RIG-I/MDA5，是抗病毒反应的关键介质。在这里，我们筛选协同的药物-病毒疗法组合，发现呼肠孤病毒III型迪尔林株（Rt3D）-帕博西尼组合增强溶瘤病毒诱导的应激反应，并增加干扰素的产生和信号传导。来自RIG-I激动剂和内质网应激诱导剂的数据进一步证实了RNA传感和内质网应激在诱导癌细胞死亡和干扰素产生中的相互作用。联合使用Rt3D-帕博西尼还可增加肿瘤细胞内的先天性免疫激活和IFN诱导的HLA表达，并伴有表观遗传格局和内源性逆转录病毒（ERV）元件的改变。对处理后细胞的免疫肽组分析进一步揭示了HLA捕获肽的变化，包括癌症或睾丸抗原及ERVs肽表达的改变。因此，我们的研究结果突出了应激信号和PRR激活之间的相互作用，以介导增强的抗癌疗效。
