二维共轭高分子光催化产CO增敏肿瘤免疫治疗的应用及机制研究

Tumor-associated immunosuppression and escape mechanisms, induced inferior presentation of tumor antigens to the relevant lymphocytes, and have severely limited their clinical results. Immunogenic cell death (ICD) can activate the immune signaling pathways and then induce the anti-tumor immune responses. This potential mechanism plays a key role in the therapeutic effects of the conventional anticancer treatments, especially in preventing the recurrence of residual tumor cells, which in turn determines the long-term success of anticancer therapies. Chemo, radiotherapeutic et.al regimens can induced ICD, but they fail to elicit antigen-specific responses and limited methods, low immunogenicity, poor clinical outcomes et.al. Our preliminary experimental results showed that an increased expression of biochemical hallmarks of ICD were detected, when tumor cells treated with carbon monoxide (CO) combined with PTT. In this project, we will synthesize an innovative CO producing near-infrared photocatalyzed 2D conjugated polymer poly(1,3,5-tris(2-thienyl) benzene nanosheets, and regulate the size, suitable bandgaps and catalytic efficiency of nanosheets and establish characterization methods. Meanwhile, to enhance the biocompatibility and tumor targeting for biomedical applications, biomimetic membrane will be used as a camouflage on the surface of nanosheets. We will further investigate the role of CO and combined with other therapies in ICD. Abscopal and anti-metastatic effect of CO combined with other therapies (checkpoint blockers, T, NK-cell transfer therapy) will be studied. This project will provide valuable reference on the design of CO delivery systems for enhanced anti-cancer drug delivery.

肿瘤相关的免疫抑制和逃逸机制，严重减弱了肿瘤免疫治疗的临床疗效。肿瘤细胞免疫原性死亡（ICD），通过诱发机体抗肿瘤免疫效应，能显著提高肿瘤免疫治疗效果。已报道可引起ICD的策略，面临方式有限、免疫原性过低、临床效果不佳等问题。本项目围绕“如何构建原位产生一氧化碳（CO）的二维高分子材料，通过诱导ICD抑制肿瘤生长，并进一步增敏免疫治疗”展开。我们的前期研究表明，CO能够提高ROS水平，显著增强ICD标志信号分子表达，增敏ICD。在此基础上，本项目拟构建尺寸可控、高效产CO的超薄二维共轭高分子聚（1,3,5-三(2-噻吩基)苯纳米片，经仿生膜修饰后，获得肿瘤靶向特性；探讨CO联合其他疗法增强ICD及引起抗肿瘤免疫应答的相关机制；验证该策略的抗肿瘤效果，并联合免疫检查点抑制剂及T、NK细胞转输等来抑制肿瘤转移。本研究将为二维高分子生物材料构建、体内气体递送及肿瘤免疫治疗提供新的策略和理论依据。

肿瘤相关的免疫抑制和逃逸机制严重限制了肿瘤免疫治疗的临床疗效。肿瘤细胞免疫原性死亡（ICD）通过诱导机体抗肿瘤免疫效应，能够显著提高了肿瘤免疫治疗的效果。已报道的可引起ICD的策略目前面临方式有限、免疫原性过低、临床效果不佳等问题。本项目围绕“如何构建原位产生一氧化氮（NO）的高分子材料，通过诱导ICD效应增敏肿瘤免疫治疗”展开。首先验证了气体分子NO能够诱导多种肿瘤细胞发生ICD效应，其是通过诱导内质网应激和线粒体功能障碍的分子机制从而引发损伤相关分子模式的释放，进一步引起机体肿瘤抗原特异免疫反应，诱导了强而持久的免疫保护作用。在此基础上，我们构建了基于聚亚硝基酯的高分子材料，在肿瘤原位可控的释放NO。研究结果表明该高分子材料能够提高NO在肿瘤组织的富集，并在还原性肿瘤微环境刺激下可控的释放NO，从而增强肿瘤治疗效果；在多种肿瘤模型中证实聚亚硝基聚酯高分子载体能够显著增强肿瘤抑制效果。我们发现，利用该载体联合PD-1能够发挥协同抗肿瘤效应，并显著抑制肿瘤转移。此外，我们还设计了聚N-亚硝胺香豆素联合光敏剂的高分子材料，在肿瘤乏氧环境中，其能在红光触发下高效释放NO，高效诱导ICD效应，激活抗原提呈细胞，并逆转乏氧微环境的免疫抑制，从而增敏肿瘤治疗。该策略为解决免疫治疗方案中肿瘤氧异质性引起的困难开辟了新的解决方法。基于上述研究，项目负责人在ACS Nano、Nano Today、Adv. Funct. Mater.、Biomaterials等高水平杂志发表论文8篇，其中IF>10论文8篇；申请中国发明专利2项，其中授权1项；论文发表、专利申请数量以及论文质量均超过项目既定目标。本项目的成功实施有望为气体用于肿瘤免疫治疗和NO高分子递送技术的发展提供新思路。