肿瘤微环境
免疫系统
癌症研究
生物
TFEB
mTORC1型
先天免疫系统
巨噬细胞
细胞生物学
获得性免疫系统
免疫学
转录因子
体外
信号转导
PI3K/AKT/mTOR通路
生物化学
基因
作者
Degao Chen,Jing Xie,Roland Fiskesund,Wenqian Dong,Xiaoyu Liang,Jiadi Lv,Xun Jin,Jinyan Liu,Siqi Mo,Tianzhen Zhang,Feiran Cheng,Yabo Zhou,Huafeng Zhang,Ke Tang,Jingwei Ma,Yuying Liu,Bo Huang
标识
DOI:10.1038/s41467-018-03225-9
摘要
Abstract Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca 2+ release via the lysosomal Ca 2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca 2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.
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