可喷射肿瘤微环境响应性高分子水凝胶用于肿瘤免疫治疗

Cancer immunotherapy by training or stimulating the inherent immunological system of organisms to attack tumor cells, has been progressing rapidly and shown tremendous promises as a next generation of cancer treatment strategy. However, the unique tumor microenvironment (TME) not only increases the potential of tumor migration and invasion, but also interferes the infiltration and activation of immune cells, as well as their ability to recognize and kill cancer cells, thus seriously reducing the responsiveness of immunotherapy. In this project, our goal is to develop a bio-responsive polymer based sprayable gel loaded with immune checkpoint antibodies (e.g. anti-PD-L1, anti-PD-1) by crosslinking poly(vinyl alcohol) (PVA) with bio-regulative molecular (e.g. metformin ) based ROS-labile linkers. The sprayable ROS－degradable scaffold releases therapeutics in a programmed manner within the tumor, leading to reversed immunosuppressive TME and enhanced therapeutic responses of tumors to immune checkpoint inhibitors. As the result, tumor recurrence and metastasis after primary resection of tumors could be prevented by such treatment. We will try to investigate the relationship between the regulation of TME and cancer immunotherapy, and explore an innovative strategy for effective and safe cancer immunotherapy.

免疫治疗是当前备受关注的一类新兴的肿瘤治疗策略。然而，目前临床肿瘤免疫疗法对实体瘤患者的临床响应率整体偏低，其中的原因之一是肿瘤内独特的免疫抑制微环境严重干扰了免疫细胞对肿瘤细胞的攻击。本项目中，申请人拟利用具有肿瘤微环境调节功能的二甲双胍分子与生物相容性好的聚乙烯醇通过活性氧敏感键原位交联，构建以药物分子为交联剂的肿瘤微环境响应性可喷射水凝胶。在装载免疫检查点阻断抗体（anti-PD-1/PD-L1）后，通过喷射的方法可将水凝胶覆盖在肿瘤手术后的创口上。当创口处有残留的肿瘤组织时，水凝胶可在肿瘤微环境中逐渐降解，一方面可清除微环境中的活性氧，另一方面则可先后释放二甲双胍和免疫检查点阻断抗体，实现先调节后治疗，以期在逆转肿瘤免疫抑制微环境的基础上提升肿瘤对免疫治疗的响应率，有效抑制术后残存肿瘤的生长和转移。本项目有望为肿瘤免疫治疗的优化和在辅助手术治疗中的应用提出具有一定借鉴意义的新策略。

该项目按照原计划先后成功构建了多种生物相容性好、智能响应性且能调节肿瘤微环境中炎症、微酸等微环境的水凝胶；已在多项研究中阐述了肿瘤微酸、炎症的微环境会导致免疫抑制的肿瘤微环境，促进免疫抑制型免疫细胞如 MDSC，肿瘤相关巨噬细胞在肿瘤内的富集，感染具有癌细胞杀伤功能的 T 细胞的活性；并利用具有肿瘤微环境调节功能的水凝胶，通过对肿瘤内炎症、微酸等微环境的调控，从而有效增强了抗肿瘤免疫反应，提高了肿瘤免疫治疗的疗效。项目执行期间，在 Nature Communications、Proc Natl Acad Sci USA、Matter、 Chemical Society Review 、Advanced Materials、Advanced Functional Materials、Nano Letter、Biomaterials等高水平学术期刊发表第一/通讯作者论文 17篇；申请国家发明专利 9件，授权 1件；申请获批了科技部重点研发计划青年项目一项；入选美国科睿唯安公布的“全球高被引科学家名单”（Highly Cited Researchers）（交叉学科）（2019、2021、2022）、江苏省“六大人才高峰”高层次人才（2020）、 Biomaterials Science Emerging Investigators （2020）、江苏省双创人才（2021）、MIT Technology Review Innovators Under 35（2021）、教育部青年长江学者（2021）等。