cGAMP特异性核酸酶（poxins）是一类最近被描述的蛋白质家族，专门阻碍循环GMP-AMP合成酶信号（cGAS），这是一种由细胞质病毒复制引发的重要感应器，可激活I型干扰素（IFN）产生。痘病毒（VACV）的B2R基因编码其中一种这些核酸酶。在这里，我们评估了在肿瘤溶瘤性病毒上下文中失活VACV B2核酸酶的影响。由于VACV能够激活针对肿瘤抗原的免疫反应，因此被广泛用作抗癌载体。我们旨在通过防止感染癌细胞后病毒对cGAS / STING / IRF3通路的激活，引发强有力的抗肿瘤免疫反应。激活这种途径与支配Th1细胞分化反应相关，这有利于抗肿瘤结果。删除B2R基因导致在感染肿瘤细胞后增强IRF3磷酸化和I型IFN表达，同时有效的VACV复制保持不受损失，无论是体外还是体内。在同基因小鼠肿瘤模型中，VACV cGAMP特异性核酸酶的缺失导致了改善的抗肿瘤活性，这与针对肿瘤表位的抗肿瘤免疫相关。 ©2023。作者。

cGAMP-specific nucleases (poxins) are a recently described family of proteins dedicated to obstructing cyclic GMP-AMP synthase signaling (cGAS), an important sensor triggered by cytoplasmic viral replication that activates type I interferon (IFN) production. The B2R gene of vaccinia viruses (VACV) codes for one of these nucleases. Here, we evaluated the effects of inactivating the VACV B2 nuclease in the context of an oncolytic VACV. VACV are widely used as anti-cancer vectors due to their capacity to activate immune responses directed against tumor antigens. We aimed to elicit robust antitumor immunity by preventing viral inactivation of the cGAS/STING/IRF3 pathway after infection of cancer cells. Activation of such a pathway is associated with a dominant T helper 1 (Th1) cell differentiation of the response, which benefits antitumor outcomes. Deletion of the B2R gene resulted in enhanced IRF3 phosphorylation and type I IFN expression after infection of tumor cells, while effective VACV replication remained unimpaired, both in vitro and in vivo. In syngeneic mouse tumor models, the absence of the VACV cGAMP-specific nuclease translated into improved antitumor activity, which was associated with antitumor immunity directed against tumor epitopes.© 2023. The Author(s).