肿瘤微环境
炎症体
免疫系统
先天免疫系统
纳米载体
安普克
癌细胞
癌症免疫疗法
上睑下垂
癌症研究
获得性免疫系统
细胞生物学
化学
生物
免疫疗法
炎症
癌症
药理学
免疫学
激酶
蛋白激酶A
遗传学
药品
作者
Long Wu,Wei Xie,Li Yang,Qiankun Ni,Peter Timashev,Meng Lyu,Ligang Xia,Yuan Zhang,Lingrong Liu,Yuan Yua,Xing‐Jie Liang,Qiqing Zhang
标识
DOI:10.1002/advs.202105376
摘要
Abstract 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.
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