Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (Togaviridae) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells.

IMPORTANCE Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 in vitro and in vivo. A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.

溶瘤病毒疗法是一种新兴的治疗方法，它使用具有复制能力的病毒来破坏癌细胞。M1是天然存在的甲病毒（Togaviridae），显示出对许多癌症有效的溶瘤活性。病毒复制过程中未折叠蛋白的积累会导致称为未折叠蛋白响应（UPR）的转录/翻译反应，这可能抵消溶瘤病毒的抗肿瘤作用。在此报告中，我们表明对IRE1α或PERK而不是ATF6的药理或生物学抑制作用大大提高了M1病毒的溶瘤作用。此外，IRE1α的抑制可阻断神经胶质瘤细胞中M1病毒诱导的自噬，从而限制M1病毒通过病毒蛋白降解而产生的抗肿瘤作用。此外，IRE1α抑制在原位神经胶质瘤模型中显着提高M1病毒的溶瘤作用。通过分子病理学研究，我们发现IRE1α在高级别神经胶质瘤中的表达水平较低，提示溶瘤病毒M1具有更高的抗肿瘤功效。综上所述，这些发现说明了神经胶质瘤细胞对溶瘤病毒M1的防御机制，并确定了增强溶瘤病毒蛋白积聚和随后肿瘤细胞裂解的可能方法。

重要性尽管溶瘤病毒疗法在临床应用中显示出广阔的前景，但并非所有患者都能从中受益。鉴定难治性癌细胞中每种溶瘤病毒的抑制信号将提供增加治疗效果的好机会。在这里，我们描述溶瘤病毒M1的感染触发了展开的蛋白反应（UPR）和随后的自噬，而阻止UPR自噬轴则显着增强了M1在体外和体内的抗肿瘤功效。对癌症组织库的一项调查显示，UPR通路中的关键元件IRE1α通常在高级别的人类神经胶质瘤中被下调，这为M1的应用提供了良好的前景。我们的工作为增强M1病毒的治疗效果提供了潜在的预测指标和目标。我们预测，基于机制的联合治疗将在未来促进癌症病毒治疗。