恶性肿瘤严重危害人类生命健康，免疫治疗成为肿瘤领域新热点。尽管基于免疫检查点的免疫治疗有一定的临床效果，但存在系统免疫过度激活导致的免疫毒性，同时肿瘤免疫耐受微环境导致肿瘤免疫治疗有效率不高。为此，本项目拟构建基于肿瘤微环境的时空次序递送VLP纳米疫苗。通过融合表达、组装策略构建表面展示肿瘤抗原和TAM靶向肽、内部携载CpG的仿病毒VLP纳米疫苗，通过化学修饰偶联肿瘤微环境响应释放的PD-L1抗体片段和PEG，实现VLP系统长循环和肿瘤靶向，到达肿瘤部位后，释放PD-L1抗体片段封闭肿瘤细胞的PD-L1，打破T细胞免疫耐受，PEG剥离后的VLP颗粒在肿瘤局部被TAM摄取，逆转M2表型，打破TAM免疫耐受，诱导T细胞活化。有效解决免疫检查点阻断抗体的系统毒性，大大提高肿瘤局部的免疫响应，提升肿瘤免疫治疗效果。

Malignant tumor is an important killer that seriously endangers human life and health. Tumor immunotherapy has become a new hotspot in the field of cancer. Although the current immunotherapy based on immune checkpoint has certain clinical therapeutic effects, there exists immune-related toxicity caused by excessive activation of the immune system. At the same time, the immune tolerance of tumor microenvironment leads to low effective tumor immunotherapy. Therefore, this project intends to fabricate a VLP nano-vaccine with spatial-temporal sequence delivery based on tumor microenvironment. Through fusion expression and assembly strategy, a novel virus-like particles (VLP) nano-vaccine was constructed to display tumor antigens and TAM targeted peptides on the surface, and carry CpG internally. PD-L1 antibody fragments and PEG were chemically conjugated on the surface, which could be released in response to tumor microenvironment. This VLP could achieve systemic long circulation and tumor targeting. After arriving at the tumor site, the released PD-L1 fragment could block the PD-L1 and broken immune tolerance of T cells. The VLP released PEG was taken up by M2, reversed the phenotype, broken TAM immune tolerance and activated T cells. It supposed that the VLP nano-vaccine could effectively solve the systemic toxicity of blocking antibodies at immune checkpoints, greatly improve the local immune response of tumor, and improve the effect of tumor immunotherapy.