Tumor Microenvironment-Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy,Advanced Materials

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Tumor Microenvironment-Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy
Advanced Materials ( IF 27.4 ) Pub Date : 2023-09-18 , DOI: 10.1002/adma.202304845
Dan Liu _{1,

2} , Shuang Liang _{1,

2} , Kongshuo Ma _{1,

2} , Qian-Fang Meng ₃ , Xingang Li ₄ , Jian Wei ₅ , Mengli Zhou _{1,

2} , Kaiqing Yun _{1,

2} , Yuanwei Pan _{3,

6} , Lang Rao ₃ , Xiaoyuan Chen _{6,

7,

8,

9} , Zhaohui Wang _{1,

2}

Affiliation

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Department of Interventional Radiography, Beijing Friendship Hospital, Capital Medical University, Beijing, 10050, China.
Department of Diagnostic Radiology, Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore.
Department of Chemical and Biomolecular Engineering and Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore.
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.

Insufficient activation of the stimulator of interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits the effect of cancer immunotherapy. Herein, tumor microenvironment (TME)-responsive nanoparticles (PMM NPs) are exploited that simultaneously harness STING and Toll-like receptor 4 (TLR4) to augment STING activation via TLR4-mediated nuclear factor-kappa B signaling pathway stimulation, leading to the increased secretion of type I interferons (i.e., 4.0-fold enhancement of IFN-β) and pro-inflammatory cytokines to promote a specific T cell immune response. Moreover, PMM NPs relieve the immunosuppression of the TME by decreasing the percentage of regulatory T cells, and polarizing M2 macrophages to the M1 type, thus creating an immune-supportive TME to unleash a cascade adaptive immune response. Combined with an anti-PD-1 antibody, synergistic efficacy is achieved in both inflamed colorectal cancer and noninflamed metastatic breast tumor models. Moreover, rechallenging tumor-free animals with homotypic cells induced complete tumor rejection, indicating the generation of systemic antitumor memory. These TME-responsive nanoparticles may open a new avenue to achieve the spatiotemporal orchestration of STING activation, providing a promising clinical candidate for next-generation cancer immunotherapy.

中文翻译：

肿瘤微环境响应性纳米颗粒放大 STING 信号通路用于癌症免疫治疗

干扰素基因刺激剂（STING）信号通路激活不足和严重的免疫抑制微环境在很大程度上限制了癌症免疫治疗的效果。在此，利用肿瘤微环境（TME）响应纳米颗粒（PMM NP）同时利用STING和Toll样受体4（TLR4）通过TLR4介导的核因子-κB信号通路刺激增强STING激活，从而增加分泌 I 型干扰素（即 IFN-β 增强 4.0 倍）和促炎细胞因子，以促进特异性 T 细胞免疫反应。此外，PMM NP 通过降低调节性 T 细胞的百分比以及将 M2 巨噬细胞极化为 M1 型来缓解 TME 的免疫抑制，从而创建免疫支持性 TME 来释放级联适应性免疫反应。与抗 PD-1 抗体相结合，可在发炎性结直肠癌和非发炎性转移性乳腺肿瘤模型中实现协同功效。此外，用同型细胞重新攻击无肿瘤动物会诱导肿瘤完全排斥，表明系统抗肿瘤记忆的产生。这些 TME 响应纳米颗粒可能为实现 STING 激活的时空协调开辟一条新途径，为下一代癌症免疫疗法提供有前景的临床候选药物。

更新日期：2023-09-18

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