Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.
Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.
复制标题
仿生纳米载体引导细胞外 ATP 稳态来重塑能量代谢，从而激活先天和适应性免疫系统
DOI：
10.1002/advs.202105376
复制
发表时间：
2022-06
期刊：
影响因子：
15.1
通讯作者：
Zhang, Qiqing
中科院分区：
文献类型：
--
作者：
Wu, Long;Xie, Wei;Li, Yang;Ni, Qiankun;Timashev, Peter;Lyu, Meng;Xia, Ligang;Zhang, Yuan;Liu, Lingrong;Yuan, Yufeng;Liang, Xing-Jie;Zhang, Qiqing
通过靶向肿瘤内失调的代谢途径进行代谢干预，在重新激活抗肿瘤免疫方面显示出了希望。然而，经批准的小分子免疫调节剂往往存在无效的应答率和严重的脱靶毒性。ATP在形成肿瘤微环境（TME）的成分的能量代谢中起着至关重要的作用，并影响癌症免疫监测。本文报道了一种纳米载体辅助免疫代谢治疗策略，该策略针对ATP -腺苷轴进行TME的代谢重编程。外泌酶（CD39）拮抗剂POM1和AMP活化蛋白激酶（AMPK）激动剂二甲双胍都被包裹在癌细胞来源的外泌体中，并用作肿瘤靶向递送的纳米载体。这种方法增加促炎细胞外ATP （eATP）的水平，同时防止免疫抑制腺苷的积累并缓解缺氧。升高的eATP触发P2X7‐NLRP3‐炎性体的激活，驱动巨噬细胞焦亡，增强树突状细胞（dc）的成熟和抗原能力，增强T细胞和自然杀伤细胞（NK）的细胞毒性功能。因此，协同抗肿瘤免疫反应被启动，以抑制肿瘤进展，抑制肿瘤远处转移，提供长期免疫记忆，提供防止肿瘤复发和克服抗PD1耐药性的保护。总的来说，这项研究提供了一种创新的策略来推进eATP驱动的抗肿瘤免疫在癌症治疗中的应用。CD39拮抗剂POM1和AMPK激动剂二甲双胍都被包裹在癌细胞来源的外泌体中，并用作肿瘤靶向递送的纳米载体。这种方法增加促炎细胞外ATP的水平，同时防止免疫抑制腺苷的积累，缓解缺氧，从而引发强烈的免疫反应，抑制肿瘤的生长、转移和复发。
Metabolic interventions via targeting intratumoral dysregulated metabolism pathways have shown promise in reinvigorating antitumor immunity. However, approved small molecule immunomodulators often suffer from ineffective response rates and severe off‐target toxicity. ATP occupies a crucial role in energy metabolism of components that form the tumor microenvironment (TME) and influences cancer immunosurveillance. Here, a nanocarrier‐assisted immunometabolic therapy strategy that targets the ATP‐adenosine axis for metabolic reprogramming of TME is reported. An ecto‐enzyme (CD39) antagonist POM1 and AMP‐activated protein kinase (AMPK) agonist metformin are both encapsulated into cancer cell‐derived exosomes and used as nanocarriers for tumor targeting delivery. This method increases the level of pro‐inflammatory extracellular ATP (eATP) while preventing the accumulation of immunosuppressive adenosine and alleviating hypoxia. Elevated eATP triggers the activation of P2X7‐NLRP3‐inflammasome to drive macrophage pyroptosis, potentiates the maturation and antigen capacity of dendritic cells (DCs) to enhance the cytotoxic function of T cells and natural killer (NK) cells. As a result, synergistic antitumor immune responses are initiated to suppress tumor progress, inhibit tumor distant metastases, provide long‐term immune memory that offers protection against tumor recurrence and overcome anti‐PD1 resistance. Overall, this study provides an innovative strategy to advance eATP‐driven antitumor immunity in cancer therapy. CD39 antagonist POM1 and AMPK agonist metformin are both encapsulated into cancer cell‐derived exosomes and used as nanocarriers for tumor targeting delivery. This method increases the level of pro‐inflammatory extracellular ATP while preventing the accumulation of immunosuppressive adenosine and alleviating hypoxia, thereby eliciting strong immune responses to inhibit tumor growth, metastasis, and recurrence.
登录
查看更多内容
影响因子：
25.7
作者：
Savio LEB;de Andrade Mello P;Figliuolo VR;de Avelar Almeida TF;Santana PT;Oliveira SDS;Silva CLM;Feldbrügge L;Csizmadia E;Minshall RD;Longhi MS;Wu Y;Robson SC;Coutinho-Silva R
通讯作者：
Coutinho-Silva R
影响因子：
8.7
作者：
Allard B;Longhi MS;Robson SC;Stagg J
通讯作者：
Stagg J
DOI：
10.1002/exp.20210008
发表时间：
2021-08
期刊：
Exploration (Beijing, China)
影响因子：
--
作者：
Guo, Shuai;Li, Kun;Hu, Bo;Li, Chunhui;Zhang, Mengjie;Hussain, Abid;Wang, Xiaoxia;Cheng, Qiang;Yang, Feng;Ge, Kun;Zhang, Jinchao;Chang, Jin;Liang, Xing-Jie;Weng, Yuhua;Huang, Yuanyu
通讯作者：
Huang, Yuanyu
AMPK：代谢和线粒体稳态的监护人。
DOI：
10.1038/nrm.2017.95
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Herzig S;Shaw RJ
通讯作者：
Shaw RJ
DOI：
10.1016/j.anai.2021.03.003
发表时间：
2021-06
期刊：
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
影响因子：
--
作者：
Goleva E;Lyubchenko T;Kraehenbuehl L;Lacouture ME;Leung DYM;Kern JA
通讯作者：
Kern JA