肿瘤微环境
癌症免疫疗法
癌症研究
免疫疗法
免疫系统
刺
干扰素基因刺激剂
TLR4型
癌症
免疫学
医学
先天免疫系统
内科学
工程类
航空航天工程
作者
Dan Liú,Shuang Liang,Kongshuo Ma,Qian‐Fang Meng,Xingang Li,Jian Wei,Minghui Zhou,Kaiqing Yun,Yuanwei Pan,Lang Rao,Xiaoyuan Chen,Zhaohui Wang
标识
DOI:10.1002/adma.202304845
摘要
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.
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