Targeting the Negative Feedback of Adenosine-A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy.
Targeting the Negative Feedback of Adenosine-A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy.
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通过用于光热免疫治疗的定制纳米抑制剂靶向腺苷 A2AR 代谢途径的负反馈
DOI：
10.1002/advs.202104182
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发表时间：
2022-05
期刊：
影响因子：
15.1
通讯作者：
Li, Yongyong
中科院分区：
文献类型：
--
作者：
Liu, Yiqiong;Liu, Ying;Xu, Dailin;Zang, Jie;Zheng, Xiao;Zhao, Yuge;Li, Yan;He, Ruiqing;Ruan, Shuangrong;Dong, Haiqing;Gu, Jingjing;Yang, Yan;Cheng, Qian;Li, Yongyong
关键词：
代谢产物腺苷通过与代谢检查点腺苷2A受体（A2 AR）连接，在肿瘤微环境（TME）中发挥重要的免疫抑制作用。在这里，在光热诱导的免疫原性细胞死亡（ICD）期间突出显示了腺苷-A2 AR负反馈途径。由ATP水解的腺苷在光热诱导的ICD过程中被放大。有可能通过靶向腺苷-A2 AR代谢途径实现稳健的基于ICD的免疫治疗。在这方面，由酸敏感性PEG壳掩蔽的负载A2 AR抑制剂的聚多巴胺纳米载体被设计成能够同时实现肿瘤特异性递送和光热诱导的ICD。在到达酸性TME时，PEG壳选择性地分离并暴露粘附性聚多巴胺层，导致抑制剂在肿瘤组织处积聚。积累的抑制剂减弱腺苷的代谢抑制作用并加强ICD免疫应答。它通过促进树突状细胞（DC）活化，增加CD 8 + T淋巴细胞浸润和减少髓源性抑制细胞（MDSC）群体而发生。此外，这种协同疗法显著地使原发性肿瘤消退，抑制远端肿瘤生长，并防止肺转移。该研究强调了一种通过使用先进的纳米材料阻断代谢检查点A2 AR来增强ICD免疫治疗效果的策略。在本研究中，验证了光热疗法（PTT）诱导的免疫原性细胞死亡（ICD）期间腺苷2A受体（A2 AR）负反馈通路的存在。由酸敏感性PEG壳掩蔽的负载A2 AR抑制剂的聚多巴胺纳米载体被设计为同时实现肿瘤特异性抑制剂递送和光热效应诱导的ICD。该策略减弱腺苷的代谢抑制作用，并有效地加强ICD免疫反应。
The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine‐A2AR negative feedback pathway is highlighted during photothermal‐induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal‐induced ICD process. It is possible to achieve a robust ICD‐based immunotherapy via targeting the adenosine‐A2AR metabolic pathway. In this regard, an A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to enable tumor‐specific delivery and photothermal‐induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8+ T lymphocyte infiltration, and reducing the myeloid‐derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials. In this study, the existence of the adenosine 2A receptor (A2AR) negative feedback pathway during photothermal therapy (PTT)‐induced immunogenic cell death (ICD) is validated. An A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to simultaneously enable tumor‐specific inhibitor delivery and photothermal effect‐induced ICD. The strategy attenuates adenosine's metabolically suppressive effects and effectively strengthens the ICD immune response.
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影响因子：
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作者：
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通讯作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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