Abstract：
Malignant pleural effusions (MPEs) are hard to treat, and their onset usually signals terminal cancer. Immunotherapies hold promise but must overcome the immunosuppressive MPE microenvironment. Herein, we treat MPEs via synergistically combining two emerging cancer therapy modalities: enzyme-dynamic therapy (EDT) and metalloimmunotherapy. To do so, a nanoplatform termed \"A-R-SOME\" was developed which comprises MPE-targeted M1 type extracellular vesicles (EVs) loaded with (1) a manganese-based superoxide dismutase (SOD) enzyme, (2) stimulator of interferon genes (STING) agonist diABZI-2, and (3) signal transducer and an activator of transcription 3 (STAT3) small interfering RNA. Endogenous reactive oxygen species within tumors induced immunogenic cell death by EDT, along with STING activation by both Mn and diABZI-2, and suppression of the STAT3 pathway. Systemically administered A-R-SOME alleviated the MPE immunosuppressive microenvironment, triggered antitumor systemic immunity, and long-term immune memory, leading to the complete eradication of MPE and pleural tumors with 100% survival rate in an aggressive murine model. A-R-SOME-induced immune effects were also observed in human patient-derived MPE, pointing toward the translation potential of A-R-SOME as an experimental malignancy treatment.
摘要：
恶性胸腔积液（MPEs）难以治疗，它们的发作通常是晚期癌症的信号。免疫疗法具有希望，但必须克服免疫抑制性MPE微环境。在这里，我们通过两种新兴的癌症治疗模式:酶动力疗法(EDT)和金属免疫疗法的协同组合来治疗MPEs.要做到这一点，开发了一种称为“A-R-SOME”的纳米平台，该平台包括MPE靶向的M1型细胞外囊泡（EVs），负载有（1）基于锰的超氧化物歧化酶（SOD）酶，（2）干扰素基因刺激因子（STING）激动剂diABZI-2，（3）信号转导和转录激活因子3（STAT3）小干扰RNA。肿瘤内内源性活性氧通过EDT诱导免疫原性细胞死亡，以及Mn和diABZI-2的STING激活，以及STAT3途径的抑制。全身给药A-R-SOME缓解了MPE免疫抑制微环境，引发抗肿瘤全身免疫，和长期免疫记忆，导致完全根除MPE和胸膜肿瘤，在侵袭性小鼠模型中存活率为100％。在人类患者来源的MPE中也观察到A-R-SOME诱导的免疫效应，指向A-R-SOME作为实验性恶性肿瘤治疗的翻译潜力。
