Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel.
Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel.
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DOI：
10.1038/s41551-020-0597-7
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发表时间：
2020-11
影响因子：
28.1
通讯作者：
Cui H
中科院分区：
文献类型：
--
作者：
Wang F;Su H;Xu D;Dai W;Zhang W;Wang Z;Anderson CF;Zheng M;Oh R;Wan F;Cui H
具有免疫抑制微环境的肿瘤对治疗反应较差。干扰素基因刺激因子（STING）通路的激活可以增强肿瘤内免疫激活，但是STING激动剂与高毒性相关并且过早降解，这限制了它们的有效性。在这里，我们表明STING激动剂环状二AMP的延长的肿瘤内释放将肿瘤微环境从免疫抑制转变为免疫刺激，从而提高了抗肿瘤治疗的疗效。STING激动剂与包含肽-药物缀合物（与在肿瘤中高度表达的蛋白质神经纤毛蛋白-1结合的肽和化疗剂喜树碱）的纳米管静电复合，所述肽-药物缀合物原位自组装成超分子水凝胶。在小鼠肿瘤的多种小鼠模型中，单次低剂量的STING激动剂导致肿瘤消退和动物存活率增加，以及长期免疫记忆和全身免疫监视，从而保护小鼠免受肿瘤复发和转移的形成。局部递送的STING激动剂可以帮助减少肿瘤免疫抑制并增强广泛的癌症治疗的功效。
Tumours with an immunosuppressive microenvironment respond poorly to therapy. Activation of the stimulator of interferon genes (STING) pathway can enhance intratumoural immune activation, but STING agonists are associated with high toxicity and degrade prematurely, which limits their effectiveness. Here, we show that the extended intratumoural release of the STING agonist cyclic di-AMP transforms the tumour microenvironment from immunosuppressive to immunostimulatory, increasing the efficacy of antitumour therapies. The STING agonist was electrostatically complexed with nanotubes comprising a peptide–drug conjugate (a peptide that binds to the protein neuropilin-1, which is highly expressed in tumours, and the chemotherapeutic agent camptothecin) that self-assemble in situ into a supramolecular hydrogel. In multiple mouse models of murine tumours, a single low dose of the STING agonist led to tumour regression and increased animal survival, and to long-term immunological memory and systemic immune surveillance, which protected the mice against tumour recurrence and the formation of metastases. Locally delivered STING agonists could help to reduce tumour immunosuppression and enhance the efficacy of a wide range of cancer therapies.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
DOI：
10.1073/pnas.1801910115
发表时间：
2018-08-07
影响因子：
11.1
作者：
Deng W;Lira V;Hudson TE;Lemmens EE;Hanson WG;Flores R;Barajas G;Katibah GE;Desbien AL;Lauer P;Leong ML;Portnoy DA;Dubensky TW Jr
通讯作者：
Dubensky TW Jr
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1039/c3cc49453e
发表时间：
2014-06-07
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Cheetham AG;Ou YC;Zhang P;Cui H
通讯作者：
Cui H