改善肿瘤乏氧微环境结合CSF-1R抑制剂协同调控巨噬细胞转变并抑制肿瘤进展

肿瘤相关巨噬细胞（TAM）作为一种重要的肿瘤浸润免疫细胞，参与了肿瘤发生和演进的整个过程。但一味地消除TAM的治疗方式会导致免疫抑制细胞的大量堆积从而对免疫系统造成巨大攻击力。本项目拟设计并制备三种双层多功能纳米粒子用于协同调控TAM表型去代替直接杀伤疗法，该纳米粒子以透明质酸-全氟丁酸（HA-PF）作为外壳，可在肿瘤组织中透明质酸酶作用下迅速裂解并释放出氧气和改变血管药物，分别通过提高氧含量、增加血管通透性和促进血管正常化达到改善肿瘤乏氧状态的目的。外壳裂解后同时释放出来的内核可进一步靶向TAM/M2并释放CSF-1R抑制剂，将免疫抑制性TAM/M2转变成免疫激活性TAM/M1。内核和外壳可协同逆转肿瘤免疫抑制状态和增强抗肿瘤免疫效应，同时本项目将系统分析肿瘤乏氧微环境产生的机制，筛选出逆转肿瘤免疫抑制状态的最佳方式，从而优化肿瘤免疫治疗手段。

Tumor-associated macrophages (TAMs), as an important class of tumor-infiltrating immune cells, are involved in the occurrence and progress of tumor. However, therapies aiming to eliminate TAMs in large numbers will lead to the recruitment of more immunosuppressive cells, which will cause tremendous damage to immune system. In this project, we intend to design and synthesize three kinds of double-layered multifunctional nanoparticles to modify the phenotype of TAMs instead of directly killing them. The nanoparticles are fabricated with a shell of hyaluronic-perfluorobutanoicaid (HA-PF), which will be degraded at the presence of hyaluronidase in tumor tissue, and release oxygen and drugs. In this way, the hypoxia state of tumor microenvironment can be reversed by the increased oxygen content, improved permeability of tumor blood vessels, and the normalization of tumor blood vessels. Moreover, the released core can target the TAM/M2 and release CSF-1R inhibitor, switching the immunosuppressive TAM/M2 to immune-activated TAM/M1. The payloads in the shell and core of nanoparticles have a synergistic effect on reversing the immunosuppressive state and enhancing the immune response in tumor. Subsequently, we will systemically analyze the mechanism of hypoxia microenvironment and screen the optimal method of reversing tumor immunosuppression to optimize tumor immunotherapy.