A Manganese Phosphate Nanocluster Activates the cGAS-STING Pathway for Enhanced Cancer Immunotherapy
A Manganese Phosphate Nanocluster Activates the cGAS-STING Pathway for Enhanced Cancer Immunotherapy
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DOI：
10.1002/adtp.202100065
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发表时间：
2021-06-09
影响因子：
4.6
通讯作者：
Tang, Li
中科院分区：
文献类型：
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作者：
Gao, Min;Xie, Yu-Qing;Tang, Li
利用天然的干扰素基因激动剂环二核苷酸（cdn）靶向干扰素基因刺激因子（STING）通路是一种很有前景的癌症免疫治疗策略。然而，天然cdn作为治疗药物的临床应用受到其固有特性（包括负电荷、小分子量和对酶降解的高敏感性）的极大阻碍。最近发现Mn2+离子可以直接激活环GMP-AMP （cGAMP）合成酶（cGAS）并增强cGAMP- sting的结合亲和力。在这里，聚乙二醇化磷酸锰（MnP-PEG）纳米团簇具有高生物相容性和有效的刺激cGAS-STING途径的能力。MnP-PEG纳米团簇激活未成熟骨髓来源的树突状细胞（DCs），导致干扰素β和白细胞介素-6的产量分别比游离cGAMP高57.3倍和13.3倍。这种强大的STING激活能力可能是由于dc对MnP-PEG纳米簇的有效细胞内化以及酸触发的内溶酶体中Mn2+离子的释放。瘤内给药MnP-PEG纳米簇可显著增强肿瘤浸润、dc和巨噬细胞的成熟，促进肿瘤中T细胞和自然杀伤细胞的活化和细胞毒性。MnP-PEG纳米簇与检查点抑制剂联合在B16F10小鼠黑色素瘤模型中导致肿瘤显著消退，而没有任何明显的毒性。
Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn2+ ions have been recently discovered to directly activate the cyclic GMP-AMP (cGAMP) synthase (cGAS) and augment cGAMP-STING binding affinity. Here, a PEGylated manganese(II) phosphate (MnP-PEG) nanocluster is developed with high biocompatibility and potent capacity to stimulate the cGAS-STING pathway. MnP-PEG nanoclusters activate the immature bone marrow-derived dendritic cells (DCs) leading to 57.3- and 13.3-fold higher production of interferon beta and interleukin-6 than free cGAMP, respectively. The potent STING activation capacity is likely due to the efficient cellular internalization of MnP-PEG nanoclusters by DCs and acid-triggered release of Mn2+ ions in the endolysosomes. Intratumoral administration of MnP-PEG nanoclusters markedly enhances tumor infiltration as well as maturation of DCs and macrophages, and promotes activation and cytotoxicity of T cells and natural killer cells in the tumor. MnP-PEG nanocluster in combination with a checkpoint inhibitor leads to significant tumor regression in the B16F10 murine melanoma model without any overt toxicities.