具有缓解肿瘤乏氧功能的纳米杂化材料在增强肿瘤免疫治疗中的作用机制研究

Tumor microenvironment controls tumor invasion and metastasis. As one of the ubiquitous features of tumor microenvironment, tumor hypoxia up-regulates kinds of cytokines, including HIF-α, etc. in tumor cells, and promotes tumor metastasis. Alleviation of tumor hypoxia can not only regulate tumor microenvironment and thus regulate the metabolic behavior of tumor cells and attenuate the invasion and metastasis of cancer cells, but also enhance the efficacy of radiotherapy and immunotherapy. However, the strategy of alleviating hypoxia is still lacking, and the influence of hypoxia on the metabolic behavior and invasiveness of tumor cells has not been clarified yet. Therefore, in this project, applicants intend to construct a new hybrid nanocrystal system (PBMn) that catalyzes the hydrogen peroxide overproduced in the tumor cells to generate oxygen and investigate the alleviating effect of PBMn on tumor hypoxia, and effect on metabolic behavior, protein expression, invasion and metastasis of tumor cells. On this basis, combined with immune checkpoint inhibitors (including anti-PD-1 and anti-PD-L1 antibodies) to investigate the effect of PBMn-mediated hypoxia alleviating on the therapeutic outcome of immune checkpoint inhibitor, in particular, the inhibitory effect on tumor metastasis. Meanwhile, PBMn-mediated tumor hypoxia relieving + photothermal therapy combined with immune checkpoint inhibitor on tumor growth and metastasis was also investigated. The preliminary research results provide solid foundation for the progress of the project. and the ongoing research of this project will find out the effect of tumor microenvironment on the therapeutic outcome of immunotherapy and provide new strategy for tumor immunotherapy.

肿瘤乏氧环境使肿瘤细胞上调HIF-α等细胞因子，促进肿瘤转移。缓解肿瘤乏氧能够调控肿瘤微环境进而调控肿瘤细胞的代谢行为、侵袭性等。但缓解乏氧的策略仍然缺乏，且乏氧缓解后对肿瘤免疫治疗的影响尚未明确。因此，在本项目中，项目申请人拟在构筑高效催化肿瘤细胞中过度产生的双氧水产生氧气的杂化纳米体系(PBMn)的基础上，深入考察PBMn对肿瘤乏氧的缓解作用，并评估乏氧环境对肿瘤细胞代谢行为、蛋白表达水平和侵袭性、转移能力等的影响。在此基础上，结合免疫检查点抑制剂，考察PBMn介导肿瘤乏氧缓解是否对免疫检查点抑制剂的治疗效果产生影响，特别是对肿瘤转移的抑制效果；同时考察PBMn介导的肿瘤乏氧缓解+光热治疗联合免疫检查点抑制剂对肿瘤生长、转移的抑制效果。前期研究成果为项目的顺利进行提供了工作基础。本项目的顺利实施将为研究肿瘤微环境对肿瘤免疫治疗的影响提供理论指导，并为肿瘤免疫治疗提供新策略。

肿瘤细胞在生长过程中由于代谢过程紊乱而具有独特的生理微环境，其中乏氧是其微环境的主要特征之一。乏氧环境对肿瘤的生长及侵袭转移具有促进作用。已有研究结果表明，缓解肿瘤组织的乏氧能够增强肿瘤免疫治疗效果（如增强免疫检查点（PD-1/PD-L1等）阻断的肿瘤免疫治疗）。常用的缓解肿瘤乏氧药物并不为肿瘤提供额外的氧气，并且由于无选择性，存在进一步抑制了免疫细胞对肿瘤细胞的免疫响应的可能。需开发更理想的肿瘤乏氧缓解策略，并建立有效控制肿瘤转移的治疗策略。基于此，本研究团队在完成杂化纳米体系PBMn的构建及功能优化，还开展并完成了其他系列的杂化纳米体系，其中包括PBMn杂化纳米体系的延伸—PBMnCu杂化纳米颗粒，PCEC包裹的Fe3O4纳米粒，硫化银纳米体系，超小硫化铜纳米体系，多孔金铂纳米体系，及小分子自组装纳米体系，并对以上纳米体系在增强肿瘤免疫治疗中的应用进行了深入研究，研究结果进一步证实了杂化纳米体系在肿瘤免疫调控及增强抗肿瘤免疫响应的潜力。项目基本按照原定的研究计划顺利进行，并取得一系列研究成果，研究成果以学术论文及专利的形式进行体现，在Advanced Functional Materials, Advanced Science, Advanced Drug Delivery Reviews, Journal of Controlled Release, Biomaterials, Acta Pharmaceutical Sinica B,ACS Applied Materials & Interfaces, Carbohydrate Polymers等国内外相关学术期刊发表学术论文12篇，其中项目负责人以第一或通讯作者身份发表学术论文10篇（篇均影响因子大于10），以主研人员身份发表学术论文2篇。此外，还有专利授权1项。该项目取得的研究成果为后续研究金属纳米体系对肿瘤免疫微环境的影响提供了指导。