血管生成是恶性肿瘤的特征之一，异常肿瘤血管的持续生成是导致肿瘤治疗耐药的重要因素。 EB 病毒 (EBV) 是一种高度流行的 DNA 致癌病毒，与各种上皮恶性肿瘤的发生有关。然而，EBV感染与肿瘤血管异常之间的关系及其潜在机制仍不清楚。在本研究中，我们发现，与未感染EBV的肿瘤相比，在临床患者肿瘤样本和小鼠异种移植模型中，EBV感染的肿瘤血管生成更多，但新生血管大多是没有周细胞附着的未成熟血管；这些未成熟的血管表现出异常的功能，其特征是血液灌注不良和血管通透性增加。 EBV感染引起的血管异常加剧了肿瘤缺氧，并加速了肿瘤的生长。从机制上讲，EBV 感染上调 ANXA3-HIF-1α-VEGF 通路。沉默 ANXA3 基因或用抗体中和 ANXA3 可以减少血管异常，从而增加免疫细胞浸润并减轻治疗耐药性。最后，一种结合 ANXA3 阻断剂和 NK 细胞 PD1 抗体的新疗法显着抑制了小鼠体内 EBV 感染的异种移植物的生长。总之，我们的研究确定了 EBV 感染在肿瘤血管异常中先前未被认识的作用，并揭示了其上调 ANXA3-HIF-1α-VEGF 通路的潜在机制。 ANXA3 是 EBV 感染肿瘤的潜在治疗靶点，通过阻断 ANXA3 来改善血管状况，与 NK 细胞 PD1 抗体疗法相结合，有望成为 EBV 相关上皮恶性肿瘤的有效治疗策略。© 2024。作者，获得施普林格自然有限公司的独家许可。

Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.