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用于使肿瘤对 PD-1 检查点阻断免疫疗法敏感的酚类免疫原性细胞死亡纳米诱导剂。

Phenolic immunogenic cell death nanoinducer for sensitizing tumor to PD-1 checkpoint blockade immunotherapy.

机构信息

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.

出版信息

Biomaterials. 2021 Feb;269:120638. doi: 10.1016/j.biomaterials.2020.120638. Epub 2020 Dec 30.


DOI:10.1016/j.biomaterials.2020.120638
PMID:33421711
Abstract

A critical challenge remains in PD-1 checkpoint blockade immunotherapy is few tumor specific T cells infiltration in hypoxic tumor microenvironment (TME). Improving immunogenic cell death (ICD) associated immunogenicity can make tumor sensitive to PD-1 checkpoint blockade immunotherapy. Herein, a phenolic ICD inducer was engineered by self-assembly of the superior ICD inducer (doxorubicin, DOX), phenolic manganese dioxide nanoreactor, ferric iron and PEG-polyphenols (MDP NPs) via metal phenolic coordination. These oxygen self-supporting MDP NPs strengthen DOX based ROS-dependent cell death and their metal mediated chemodynamic effect accelerate ICD induction. Together with concomitant ICD triggered by DOX, MDP NPs successively lead to tumor-associated antigen boosting, DCs maturation and ultimately enhance tumor-specific T cells infiltration. Furthermore, MDP NPs efficiently modulated hypoxic TME for effective macrophages recruitment. This promising ICD-augment strategy efficiently improve tumor response to PD-1 checkpoint blockade immunotherapy, resulting in a significant antitumor immune response in primary tumor and a strong abscopal effect to distant tumor. Our simple and versatile phenolic inducer expands the application of chemodrugs based ICD enhancing PD-1 checkpoint blockade immunotherapy.

摘要

在 PD-1 检查点阻断免疫疗法中,一个关键的挑战是缺氧肿瘤微环境 (TME) 中浸润的肿瘤特异性 T 细胞较少。提高与免疫原性细胞死亡 (ICD) 相关的免疫原性可以使肿瘤对 PD-1 检查点阻断免疫疗法敏感。在此,通过金属酚配位,将 superior ICD 诱导剂(阿霉素,DOX)、酚型二氧化锰纳米反应器、铁和 PEG-多酚自组装成一种酚型 ICD 诱导剂 (MDP NPs)。这些自供氧的 MDP NPs 增强了基于 DOX 的 ROS 依赖性细胞死亡,其金属介导的化学动力学效应加速了 ICD 的诱导。与 DOX 引发的伴随 ICD 一起,MDP NPs 成功地增强了肿瘤相关抗原,促进了 DCs 的成熟,并最终增强了肿瘤特异性 T 细胞的浸润。此外,MDP NPs 有效地调节了缺氧的 TME,以有效招募巨噬细胞。这种有前景的 ICD 增强策略可有效提高肿瘤对 PD-1 检查点阻断免疫疗法的反应,从而在原发性肿瘤中产生强烈的抗肿瘤免疫反应,并对远处肿瘤产生强烈的远隔效应。我们简单而通用的酚诱导剂扩展了基于 chemodrugs 的 ICD 增强 PD-1 检查点阻断免疫疗法的应用。

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Phenolic immunogenic cell death nanoinducer for sensitizing tumor to PD-1 checkpoint blockade immunotherapy.

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