Oncolytic viruses (OVs) can selectively replicate in tumor cells and remodel the microenvironment of immunologically cold tumors, making them a promising strategy to evoke antitumor immunity. Similarly, agonists of the stimulator of interferon genes (STING)‐interferon (IFN) pathway, the main cellular antiviral system, provide antitumor benefits by inducing the activation of dendritic cells (DC). Considering how the activation of the STING‐IFN pathway could potentially inhibit OV replication, the use of STING agonists alongside OV therapy remains largely unexplored. Here, we explored the antitumor efficacy of combining an HSV‐1‐based OV, C‐REV, with a membrane‐impermeable STING agonist, 2′3′‐GAMP. Our results demonstrated that tumor cells harbor a largely defective STING‐IFN pathway, thereby preventing significant antiviral IFN induction regardless of the permeability of the STING agonist. In vivo, the combination therapy induced more proliferative KLRG1‐high PD1‐low CD8+ T‐cells and activated CD103+ DC in the tumor site and increased tumor‐specific CD44+ CD8+ T‐cells in the lymph node. Overall, the combination therapy of C‐REV with 2′3′‐cGAMP elicited antitumor immune memory responses and significantly enhanced systemic antitumor immunity in both treated and non‐treated distal tumors.

中文翻译：

---

STING 激活剂 2′3′-cGAMP 增强基于 HSV-1 的溶瘤病毒治疗

溶瘤病毒（OV）可以选择性地在肿瘤细胞中复制并重塑免疫冷肿瘤的微环境，使其成为激发抗肿瘤免疫的有前途的策略。同样，干扰素基因刺激剂 (STING)-干扰素 (IFN) 通路（主要的细胞抗病毒系统）的激动剂通过诱导树突状细胞 (DC) 的激活来提供抗肿瘤益处。考虑到 STING-IFN 通路的激活如何可能抑制 OV 复制，STING 激动剂与 OV 治疗一起使用在很大程度上仍未得到探索。在这里，我们探讨了基于 HSV-1 的 OV（C-REV）与膜不可渗透的 STING 激动剂 2'3'-GAMP 组合的抗肿瘤功效。我们的结果表明，肿瘤细胞具有很大程度上有缺陷的 STING-IFN 通路，从而阻止了显着的抗病毒 IFN 诱导，无论 STING 激动剂的渗透性如何。体内，联合疗法诱导更多的增殖 KLRG1-高 PD1-低 CD8+T 细胞和活化的 CD103+肿瘤部位的 DC 和肿瘤特异性 CD44 增加+CD8+淋巴结中的 T 细胞。总体而言，C-REV 与 2'3'-cGAMP 联合治疗可引发抗肿瘤免疫记忆反应，并显着增强治疗和未治疗远端肿瘤的全身抗肿瘤免疫。