基于肿瘤新生抗原的免疫疗法已取得突破进展，开启了肿瘤免疫治疗新时代。但存在新生抗原不表达至肿瘤细胞表面，免疫效应细胞无法识别的漏洞，导致患者响应低，亟需新思路提高疗效。本课题首创新生抗原特异性再标记理念，构建三维-定促合一纳米凝胶将新生抗原特异标记到肿瘤细胞表面，实施“制导集火”肿瘤免疫治疗新策略。该纳米凝胶以NGR介导靶向至肿瘤，MMP2敏感降解，释放载pB16M27-GPI纳米粒PPMB、载CpG纳米粒PMC及B7H3单抗。PPMB靶向肿瘤细胞并将新生抗原B16M27锚定于细胞膜，实现肿瘤细胞再标记；B7H3单抗解除NK和T细胞抑制，PMC靶向激活TAM，三种效应细胞共同起效，将获得最大免疫治疗效益。课题针对新兴领域的热点问题，首创新生抗原特异性再标记新理念，实践“制导集火”肿瘤免疫治疗新策略，旨在通过独辟蹊径取得开拓性成果，大力推动我国肿瘤免疫治疗研究的深入发展。

Tumor neoantigen-based immunotherapy has made great breakthroughs in recent years and opened a new era for tumor immunotherapy. However, there were still patients with low responses and new solutions were urgent needed. The main challenge was that some neoantigen couldn’t be successfully expressed on the tumor cell surface, so it was hard for immune effector cells to recognize these tumor cells, thus, the immunotherapy failed. Hence, in this study, we created “tumor neoantigen remarking” concept to artificially label the tumor cells with the specific neoantigen. In this project, targeting-triggering three dimensional nanogel would be constructed to implement the “guide-gank” tumor immunotherapy based on “tumor neoantigen remarking” concept. The targeting-triggering three dimensional nanogel was delivered to the tumor tissue through NGR mediated active targeting. The naogel was enzyme sensitively disintegrated by MMP-2 in the tumor microenvironment, then the pB16M27-GPI loaded nanoparticles (PPMB), CpG loaded nanoparticles (PMC) and B7H3 monoclonal antibody were released. PPMB could be actively targeted to tumor cells, the loaded pB16M27-GPI were released and the tumor neoantigen B16M27 were expressed on the cell membrane with the help of membrane anchoring peptide GPI to achieve tumor neoantigen remarking. B7H3 monoclonal antibody could relieve the inhibition of tumor on NK and T cell. PMC could be targeted to TAM and activate TAM. Thus, the CTL, NK and TAM cells would be all inspired and enhanced tumor immunotherapy efficacy could be ensured. This project is focusing on the hot issues of tumor neoantigen-based immunotherapy fields, and the novel “tumor neoantigen remarking” concept is firstly issued. This new therapeutic concept offers a very powerful means of fixing the vulnerability. This project aims to achieve pioneering results through a unique approach, to practice the novel “guide-gunk” strategy and promote the in-depth development of tumor immunotherapy in China.