Nature BME:多价STING激动剂对天然免疫通路的长效激活

2021-02-24 MedSci原创 MedSci原创

干扰素基因刺激蛋白(STING)是一种内质网跨膜蛋白,是治疗传染病和癌症的靶点,其在对抗感染和癌症的先天免疫中起着重要的作用。

干扰素基因刺激蛋白(STING)是一种内质网跨膜蛋白,是治疗传染病和癌症的靶点,其在对抗感染和癌症的先天免疫中起着重要的作用。STING是由cGAMP内源性激活的,cGAMP是一种由cGAMP合酶(cGAS)合成的环状二核苷酸,其对细胞溶质DNA作为危险信号作出反应。STING的激活介导多方面的I型干扰素(IFN-I)反应,促进树突状细胞(DC)的成熟和迁移并激发细胞毒性T淋巴细胞和自然杀伤细胞(NK)的自发免疫反应。

近年来,在肿瘤免疫治疗中,STING已成为激活抗肿瘤免疫途径的重要靶点。而多价相缩合也已被证明可用于调节多种生物过程,包括核糖体组装、基因表达和信号转导。相分离涉及通过多价相互作用组装大分子复合物。

本文研究人员以前合成了一个具有线性或环状叔胺结构的对酸碱度敏感的聚合物库,其中一个具有环状七元环(PC7A)的聚合物通过STING依赖途径显示出很强的疫苗佐剂效应。在这篇文章中,作者团队报道了PC7A是一种多价的STING激动剂,与cGAMP相比,它通过聚合物诱导的STING相胶连来激活先天免疫反应,延长细胞因子的表达。

STING活化的程度取决于聚合物的长度,从而决定相互作用的价态。作者团队还证明了,在两种动物肿瘤模型中,负载cGAMP的PC7A纳米粒(NPs)可引起强大的肿瘤生长抑制和提高存活率,并且在切除的人类肿瘤和淋巴结中协同激活STING。

综上所述,这项研究强调了使用合成聚合物诱导STING缩合从而激活天然免疫途径发挥抗肿瘤的功效PC7A的多价STING激活与细胞内cGAMP刺激的结合进一步为癌症免疫治疗提供了一种协同和稳健的抗肿瘤免疫策略。

Li, S., Luo, M., Wang, Z. et al. Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-020-00675-9

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    2021-08-14 liye789132251
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    2021-02-26 lxg955
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