Oncolytic viruses (OVs) are emerging as a potentially useful treatment for malignancies due to the capabilities of direct oncolysis and immune induction. Improving the replication of OVs is an effective approach to enhance the oncolytic effects. Here, we observed that cancer cells with deficiencies in JAK-STAT pathway showed greater sensitivity to oncolytic adenovirus (oAd), and JAK inhibitor could enhance the replication of oAd. Therefore, we constructed a novel oAd expressing SOCS3, a major negative regulator of JAK-STAT pathway, and confirmed that oAd-SOCS3 exhibited a more significant antitumor effect than oAd-Ctrl both in vitro and in vivo. Mechanistically, SOCS3 inhibited the activation of JAK-STAT pathway, resulting in stronger tumor selective replication of oAd and downregulated expression of PD-L1 on cancer cells as well. Both benefits could collectively awaken antitumor immunity. This study highlights the importance of JAK-STAT pathway in viral replication and confirms the treatment of oAd-SOCS3 in potential clinical applications.

由于具有直接溶瘤和免疫诱导的能力，溶瘤病毒（OV）正在成为一种潜在的恶性肿瘤治疗方法。提高OVs的复制是增强溶瘤效果的有效方法。在这里，我们观察到JAK-STAT通路缺陷的癌细胞对溶瘤腺病毒（oAd）表现出更高的敏感性，而JAK抑制剂可以增强oAd的复制。因此，我们构建了一种表达JAK-STAT通路主要负调节因子SOCS3的新型oAd，并证实oAd-SOCS3在体外和体内均比oAd-Ctrl表现出更显着的抗肿瘤作用。从机制上讲，SOCS3抑制JAK-STAT通路的激活，导致oAd更强的肿瘤选择性复制，并下调癌细胞上PD-L1的表达。这两种益处可以共同唤醒抗肿瘤免疫力。这项研究强调了 JAK-STAT 通路在病毒复制中的重要性，并证实了 oAd-SOCS3 治疗的潜在临床应用。