Chronic inflammation induced by persistent viruses infection plays an essential role in tumor progression, which influenced on the interaction between the tumor cells and the tumor microenvironment. Our earlier study showed that ATR, a key kinase participant in single-stranded DNA damage response (DDR), was obviously activated by Epstein–Barr virus (EBV) in nasopharyngeal carcinoma (NPC). However, how EBV-induced ATR activation promotes NPC by influencing inflammatory microenvironment, such as tumor-associated macrophages (TAMs), remains elusive. In this study, we showed that EBV could promote the expression of p-ATR and M2-type TAMs transformation in clinical NPC specimens. The expression of p-ATR and M2-type TAMs were closely correlated each other and involved in TNM stage, lymph node metastasis and poor prognosis of the patients. In addition, the expression levels of CD68⁺CD206⁺, Arg1, VEGF, and CCL22 were increased in EB⁺ CNE1 cells, and decreased when ATR was inhibited. In the nude mice, EBV-induced ATR activation promoted subcutaneous transplanted tumor growth, higher expression of Ki67 and lung metastasis via M2-type TAMs recruitment. Experimental data also showed that the polarization of M2, the declined tumor necrosis factor-α (TNF-α) and increased transforming growth factor-β (TGF-β) were associated with ATR. Meanwhile, ATR activation could promote PPAR-δ and inhibited c-Jun and p-JNK expression, then downregulate JNK pathway. Collectively, our current study demonstrated the EBV infection could activate the ATR pathway to accelerate the transition of TAMs to M2, suggesting ATR knockdown could be a potential effective treatment strategy for EBV-positive NPC.

持续性病毒感染引起的慢性炎症在肿瘤进展中起着至关重要的作用，影响了肿瘤细胞与肿瘤微环境之间的相互作用。我们早期的研究表明，ATR 是单链 DNA 损伤反应 (DDR) 的关键激酶参与者，在鼻咽癌 (NPC) 中明显被 Epstein-Barr 病毒 (EBV) 激活。然而，EBV 诱导的 ATR 激活如何通过影响炎症微环境（如肿瘤相关巨噬细胞 (TAM)）来促进 NPC 仍然难以捉摸。在本研究中，我们发现 EBV 可以促进临床 NPC 标本中 p-ATR 和 M2 型 TAMs 转化的表达。p-ATR与M2型TAMs的表达密切相关，与TNM分期、淋巴结转移及患者预后不良有关。此外，⁺ CD206 ⁺、Arg1、VEGF 和 CCL22 在 EB ^+中增加CNE1 细胞，当 ATR 被抑制时减少。在裸鼠中，EBV 诱导的 ATR 激活通过 M2 型 TAM 募集促进了皮下移植肿瘤的生长、Ki67 的更高表达和肺转移。实验数据还表明，M2的极化、下降的肿瘤坏死因子-α（TNF-α）和增加的转化生长因子-β（TGF-β）与ATR相关。同时，ATR激活可以促进PPAR-δ，抑制c-Jun和p-JNK的表达，进而下调JNK通路。总的来说，我们目前的研究表明，EBV 感染可以激活 ATR 途径以加速 TAM 向 M2 的转变，这表明 ATR 敲低可能是 EBV 阳性 NPC 的潜在有效治疗策略。