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精确调控肿瘤微环境中的活性氧以减轻抑制性免疫原性细胞死亡

Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death.

作者信息

Xu Zichuang, He Yuchu, Zhang Xuwu, Tu Wenkang, Li Xiaoling, Wang Dong, Yan Yaqian, Gao Jiajun, Wang Desong, Gao Dawei

机构信息

State Key Laboratory of Metastable Materials Science and Technology, Applying Chemistry Key Lab of Hebei Province, Nano-Biotechnology Key Lab of Hebei Province, Yanshan University, Qinhuangdao, 066004, China.

Asymchem Life Science (Tianjin) Company Limited, Tianjin, 300457, P. R. China.

出版信息

Adv Healthc Mater. 2024 Dec;13(30):e2401741. doi: 10.1002/adhm.202401741. Epub 2024 Aug 7.


DOI:10.1002/adhm.202401741
PMID:39113330
Abstract

High level of reactive oxygen species (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.

摘要

肿瘤微环境(TME)中高水平的活性氧(ROS)不仅会损伤肿瘤细胞,还会降低免疫原性细胞死亡(ICD)的疗效以及肿瘤浸润性T淋巴细胞的活性,从而限制免疫治疗的效果。因此,精确调节ROS水平对于有效消除肿瘤细胞和激活ICD诱导的免疫治疗至关重要。在此,设计了一种智能蛋黄壳纳米平台(SPCCM),其具有碳酸钙壳,能够在酸性TME条件下分解,从而释放天然抗氧化剂原花青素(PAs)和光敏剂Ce6。PAs清除肿瘤内的ROS,延长T淋巴细胞的存活时间,而Ce6作为ICD诱导剂,在激光照射下产生高浓度的ROS,从而达到肿瘤细胞内的毒性阈值并诱导凋亡。产生的凋亡细胞作为肿瘤相关抗原,促进树突状细胞(DCs)成熟,并激活ICD。通过有效中和TME中的ROS,PAs可持续降低ROS水平,从而增强DCs的激活并恢复被ROS抑制的抗肿瘤免疫细胞活性(导致DCs激活增加八倍)。本研究通过精确调节ROS水平证明了光动力疗法和免疫疗法之间的有效协同作用。

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Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death.

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