For successful treatment of EBV-associated tumors immune tolerance must be broken. While most studies of EBV-associated tumor vaccines have focused on augmenting tumor-specific effector T cells, the effects of these vaccines on the immune-suppressive tumor microenvironment have not been investigated. Here, we describe the manufacture of a nanovaccine using tannic acid (TA) and a newly constructed protein antigen for EBV-associated tumors with interferon-α (IFN-α) or CpG as adjuvants. TA as a biocompatible material from plant self-assembles with antigens and adjuvants via hydrogen bonding to form well-defined nanoparticulate vaccines by flash nanocomplexation, a scalable yet controllable technique. By targeting lymph nodes, the nanovaccine co-loaded with CpG adjuvant induces strong immune activation and exhibits efficient inhibition tumorigenesis. Moreover, the nanovaccine combining with anti-PD-L1 results a marked decrease in tumor size and prolonged survival of tumor-bearing mice by decreasing infiltration of regulatory T cells to the tumor lesion. This suggests that the nanovaccine can reverse immune checkpoint inhibitor resistance by remodeling the tumor microenvironment. Thus, this study shows a promising strategy for treatment of EBV-positive tumors in patients.

为了成功治疗与EBV相关的肿瘤，必须打破免疫耐受性。尽管大多数与EBV相关的肿瘤疫苗的研究都集中在增加肿瘤特异性效应T细胞上，但尚未研究这些疫苗对免疫抑制肿瘤微环境的影响。在这里，我们描述了使用鞣酸（TA）和针对EBV相关肿瘤的新构建的蛋白抗原，以干扰素-α（IFN-α）或CpG为佐剂的纳米疫苗的生产。TA是一种来自植物的生物相容性材料，可通过氢键与抗原和佐剂自组装，通过快速纳米复合技术（一种可扩展但可控制的技术）形成定义明确的纳米颗粒疫苗。通过靶向淋巴结，与CpG佐剂共载的纳米疫苗诱导了强大的免疫激活并表现出有效的抑制肿瘤发生的作用。此外，与抗PD-L1结合的纳米疫苗可通过减少调节性T细胞对肿瘤病变的浸润，显着降低肿瘤大小并延长荷瘤小鼠的生存期。这表明纳米疫苗可以通过重塑肿瘤微环境来逆转免疫检查点抑制剂的耐药性。因此，本研究显示了一种有前途的治疗患者EBV阳性肿瘤的策略。