肿瘤免疫治疗通过调动免疫系统对抗癌细胞，被认为是有效控制和治愈癌症的新希望。在癌症免疫疗法中，如何实现精确、可控、高效的免疫系统激活，是能否成功抑制肿瘤生长、降低治疗副作用的关键。本项目中，我们将通过纳米颗粒结构设计，突破纳米免疫激活载体从血液循环到肿瘤部位的多重生理屏障，实现对肿瘤部位自然杀伤细胞(NK细胞)的精确激活，建立由选择性原始免疫系统激活调控适应性免疫系统协同抑制肿瘤的新型免疫治疗方法。该纳米颗粒预期实现以下特性：（1）在血液中稳定循环，不激活免疫系统；（2）协同响应肿瘤微环境 pH 变化和肿瘤细胞表面化学结构，实现对肿瘤细胞靶向并暴露出所携带 NK 细胞激活因子；（3）仅激活肿瘤周围 NK 细胞，通过此过程进一步激活适应性免疫系统，协同实现肿瘤的长效抑制。本项目将从分子水平揭示纳米颗粒对肿瘤靶向作用，探索免疫激活机理，构建高效、可控、低副作用的肿瘤免疫治疗新方法。

Cancer immunotherapy, which restore or enhance the innate powers of immune system to fight cancer, has been considered as the ultimate hope of the cure of many cancers. Towards an effective cancer immunotherapy, it is of importance to active immune cells in a precise and controllable manner, which could avoid overstimulation of immune system thus achieve safe and effective cancer treatment. In this proposal, we will demonstrate a novel approach to overcome the fast clearance of foreign particles by a rational designed nanoparticle, which can selectively activate the NK cells located around tumors to kill tumor cells without damaging other tissues and organs. We envision that this nanoparticle-based strategy will outperform current immunotherapies in the several aspects including (1) enhanced plasma stability without non-specific activation of blood NK cells that cause autoimmunity, (2) highly efficient tumor targeting by utilizing polymer responsive to the acidic tumor microenvironment as well as host-guest recognition between the nanoparticles and the surface proteins of cancer cells, and (3) selective stimulation of NK cells located at tumor sites, leading to the lysis of tumor cells as well as the activation of adaptive immunity, which could provide a long-term suppression of tumor growth. This project will also try to understand the tumor-targeting capability of nanoparticles in molecular level, and explore a new strategy for better control and activation of human immune system for a more efficient and safer cancer therapy.