Rationale: Immuno-virotherapy has emerged as a promising approach for cancer treatment, as it directly and cytotoxically eliminates tumors with systemic immune stimulation. However, the clinical efficacy of this approach remains limited by inappropriate delivery routes, robust antiviral responses, and the tumor immunosuppressive microenvironment. Methods: To address these challenges, we propose a surface engineering strategy that masks oncolytic herpes simplex virus (oHSV) with a galactose-polyethylene-glycol (PEG) polymer chain to minimize host antiviral responses and selectively targets tumors by limiting exposure to circulation upon systemic administration. We evaluated the antitumor efficacy of glycosylated-PEG-oHSV by examining tumor growth in animal models and analyzing tumor-infiltrating CD8+T cells and NK cells in the tumor microenvironment (TME). To assess the neutralizing antibody levels after systemic administration of glycosylated-PEG-oHSV, we utilized a mouse model and measured oHSV-specific IgG. Results: We demonstrate that the glycosylated-PEG modified oHSV does not affect the replication of oHSV yet exhibits high specificity to the asialoglycoprotein receptor (ASGPR) overexpressed in hepatocellular carcinoma cells. This results in selectively targeting cancer cells and deep penetration into tumors while avoiding spreading into the brain. Our approach also effectively reduces oHSV-specific neutralizing antibody levels to mitigate host antiviral immune response. Notably, our glycosylated-PEG-oHSV alleviates the immunosuppressive microenvironment within tumors by reducing regulatory T cells, augmenting the infiltration of activated CD8+T cells and NK cells with increasing release of anti-tumor cytokines, to impede tumor progression. Conclusion: Our findings offer a widely applicable and universal strategy to enhance cancer immuno-virotherapy through systemic administration of non-genetically engineered oncolytic viruses. This approach has the potential to overcome the limitations of current immune-virotherapy strategies and may improve clinical outcomes for cancer patients.

中文翻译：

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糖基化 PEG 掩蔽的溶瘤病毒的全身递送增强了抗肿瘤免疫病毒疗法的靶向性并调节 T 和 NK 细胞浸润。

理由：免疫病毒疗法已成为一种有前景的癌症治疗方法，因为它通过全身免疫刺激直接以细胞毒性方式消除肿瘤。然而，这种方法的临床疗效仍然受到不适当的递送途径、强大的抗病毒反应和肿瘤免疫抑制微环境的限制。方法：为了应对这些挑战，我们提出了一种表面工程策略，用半乳糖聚乙二醇（PEG）聚合物链掩盖溶瘤单纯疱疹病毒（oHSV），以最大限度地减少宿主抗病毒反应，并通过限制全身循环暴露来选择性靶向肿瘤行政。我们通过检查动物模型中的肿瘤生长并分析肿瘤微环境 (TME) 中的肿瘤浸润 CD8+T 细胞和 NK 细胞来评估糖基化-PEG-oHSV 的抗肿瘤功效。为了评估全身施用糖基化-PEG-oHSV后的中和抗体水平，我们利用小鼠模型并测量了oHSV特异性IgG。结果：我们证明糖基化-PEG 修饰的 oHSV 不会影响 oHSV 的复制，但对肝细胞癌细胞中过表达的脱唾液酸糖蛋白受体 (ASGPR) 表现出高度特异性。这导致选择性地靶向癌细胞并深入渗透到肿瘤中，同时避免扩散到大脑中。我们的方法还有效降低了 oHSV 特异性中和抗体水平，以减轻宿主的抗病毒免疫反应。值得注意的是，我们的糖基化-PEG-oHSV 通过减少调节性 T 细胞、增加活化 CD8+T 细胞和 NK 细胞的浸润以及增加抗肿瘤细胞因子的释放来缓解肿瘤内的免疫抑制微环境，从而阻止肿瘤进展。结论：我们的研究结果提供了一种广泛适用和通用的策略，通过全身施用非基因工程溶瘤病毒来增强癌症免疫病毒治疗。这种方法有可能克服当前免疫病毒治疗策略的局限性，并可能改善癌症患者的临床结果。