结直肠癌免疫治疗绝大多数效果不佳，原因之一可能是T细胞不能够渗透入肿瘤。在动物模型中，耗竭癌症相关成纤维细胞（CAF）可以促进T渗透。溶瘤病毒不仅直接或诱导免疫系统杀死肿瘤细胞，而且是合适的蛋白表达平台。因此，依据我们前期Ⅱ型单纯疱疹病毒OHSV2作为1类新药的研究技术基础，首先构建一种表达人BiTE双特异蛋白，靶向CAF表面分子FAP5的OHSV2-BiTE-FAP5。其次，分析杀死肿瘤细胞时，消耗CAF（非恶性细胞，遗传稳定，耐药可能性低），促进T细胞进入肿瘤，将免疫荒漠型变为免疫-热的肿瘤。不仅降低双特异蛋白系统给药的副作用，同时将抗病毒的肿瘤浸润T细胞，转变为攻击肿瘤细胞的T细胞，减少溶瘤病毒耐药。最后，分析OHSV2-BiTE-FAP5与免疫检查点抑制剂联合的协同作用，进一步验证T细胞进入肿瘤的效果。证实OHSV2-BiTE-FAP5不仅可作为新药开发，也是联合治疗的优秀平台。

The immunotherapy, such as immune-checkpoint inhibitors, for most of colorectal cancer patients is not effective. One of the reasons may be that T cells are unable to infiltrate into the tumor. In animal models, genetically depleted cancer-associated fibroblasts (CAF) can promote T penetration. Oncolytic viruses did not only directly kill tumor cells or through the immune system activation, but are also suitable protein expression platforms. Therefore, based on our previous research on herpes simplex virus OHSV2 as a new class 1 drug, we first constructed an OHSV2-BiTE-FAP5 that expresses the human BiTE bispecific protein targeting the CAF surface molecule FAP5. It kills tumor cells, and depletes CAFs (non-malignant cells, with genetic stability, and therefore less likely to acquire drug resistance), promotion of T cells into tumors, and transforms the immune desert type into an immune-hot tumor microenvironment. Secondly, OHSV2-BiTE-FAP5 not only can reduce the side effects of bispecific antibody due to systemic delivery, but also by which the antiviral tumor infiltrating T cells can be transformed into T cells that attack tumor, thereby reducing oncolytic virus resistance. .Finally, the synergistic effect of OHSV2-BiTE-FAP5 combined with immunological checkpoint inhibitors will be analyzed to further verify the effect of T cells intratumoural infiltration. It was confirmed that OHSV2-BiTE-FAP5 could not only be developed as a new drug, but also an excellent platform for combination therapy.