肿瘤细胞治疗研究
英文原题：A natural killer T cell nanoagonist-initiated immune cascade for hepatocellular carcinoma synergistic immunotherapy.
自然杀伤T（NKT）细胞介导的免疫疗法在具有固有免疫抑制微环境的肝细胞癌中显示出巨大前景。
自然杀伤T（NKT）细胞介导的免疫治疗在具有固有免疫抑制微环境的肝细胞癌中展现出巨大前景。然而，NKT细胞激动剂的靶向递送仍然具有挑战性。在此，我们开发了一种透明质酸（HA）修饰的金属有机框架（沸石咪唑酯骨架-8，ZIF-8），用于封装α-半乳糖神经酰胺（α-Galcer，一种经典的NKT细胞激动剂）和阿霉素（DOX）以消除肝癌，命名为α-Galcer/DOX@ZIF-8@HA。在肿瘤微环境（TME）中，这些pH响应性纳米框架可逐渐崩解释放α-Galcer以激活NKT细胞，并进一步促进其他免疫细胞，从而启动抗肿瘤免疫级联反应。与DOX一起，释放的α-Galcer能够在TME中有效激活NKT细胞，实现协同免疫治疗和肿瘤消除，在皮下和原位肝肿瘤模型中均导致明显的肿瘤抑制和延长动物生存期。将NKT细胞激动剂操控进入TME中的功能性纳米框架，可能与其他先进治疗手段相结合，应用于更广泛的癌症治疗。
Natural killer T (NKT) cell-mediated immunotherapy shows great promise in hepatocellular carcinoma featuring an inherent immunosuppressive microenvironment. However, targeted delivery of NKT cell agonists remains challenging. Here, we developed a hyaluronic acid (HA) modified metal organic framework (zeolitic imidazolate framework-8, ZIF-8) to encapsulate α-galactosylceramide (α-Galcer), a classic NKT cell agonist, and doxorubicin (DOX) for eliminating liver cancer, denoted as α-Galcer/DOX@ZIF-8@HA. In the tumor microenvironment (TME), these pH-responsive nano-frameworks can gradually collapse to release α-Galcer for activating NKT cells and further boosting other immune cells in order to initiate an antitumor immune cascade. Along with DOX, the released α-Galcer enabled efficient NKT cell activation in TME for synergistic immunotherapy and tumor elimination, leading to evident tumor suppression and prolonged animal survival in both subcutaneous and orthotopic liver tumor models. Manipulating NKT cell agonists into functional nano-frameworks in TME may be matched with other advanced managements applied in a wider range of cancer therapies.
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