Monocarboxylate transporter blockage-enabled lactate redistribution reshapes immunosuppressive tumor microenvironment and enhances chemodynamic immunotherapy

作者全名："Wang, Jingxue; Jiang, Weixi; Fang, Mingxiao; Du, Chier; Guo, Xun; Qiu, Xiaoling; Wang, Xiaoting; Luo, Yuanli; Tu, Peng; Cheng, Chen; Li, Pan; Ran, Haitao; Ren, Jianli"

作者地址："[Wang, Jingxue; Jiang, Weixi; Fang, Mingxiao; Du, Chier; Guo, Xun; Qiu, Xiaoling; Wang, Xiaoting; Luo, Yuanli; Tu, Peng; Cheng, Chen; Li, Pan; Ran, Haitao; Ren, Jianli] Chongqing Med Univ, Affiliated Hosp 2, Inst Ultrasound Imaging, Ultrasound Dept, Chongqing 400010, Peoples R China; [Qiu, Xiaoling] Chongqing Med Univ, Affiliated Hosp 2, Dept Intens Care Unit, Chongqing 400042, Peoples R China; [Tu, Peng] Chongqing Med Univ, Women & Childrens Hosp, Chongqing Hlth Ctr Women & Children, Dept Ultrasound, Chongqing 400013, Peoples R China"

通信作者："Ren, JL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Ultrasound Imaging, Ultrasound Dept, Chongqing 400010, Peoples R China."

来源：CHEMICAL ENGINEERING JOURNAL

ESI学科分类：ENGINEERING

WOS号：WOS:001112035400001

JCR分区：Q1

影响因子：13.3

年份：2023

卷号：477

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Chemodynamic immunotherapy; MCT inhibition; Lactate; Immunosuppressive tumor microenvironment

摘要："The immunosuppressive tumor microenvironment (TME) hinders T cells infiltration and prevents a sufficient immune response. Monocarboxylate transporter (MCT)-mediated lactate accumulation not only leads to tumor acidification but also recruits immunosuppressive cells, which greatly limits the therapeutic efficacy of immunotherapy. In this work, we report an MCT blockage strategy using a manganese-based metal organic framework (MnMOF) for enhanced chemodynamic immunotherapy. Syrosingopine (Syr) was found to prevent tumor cells from excreting lactate into the extracellular environment via MCT, thus lowering the intracellular pH and increasing the intracellular H2O2 levels. Afterward, the Mn ion-triggered Fenton-like reaction was amplified by the increased H2O2 levels and strongly acidic conditions in tumor cells. The dying tumor cells induced by chemodynamic therapy released damage-associated molecular patterns, promoting the activation and proliferation of T cells. Furthermore, Syr reduced the lactate levels of the extracellular TME to restore immune activity, including the M1 polarization of tumor-associated macrophages, the activation of dendritic cells and cytotoxic T lymphocytes, and a reduction in immunosuppressive cells. Overall, this Syr@PEG-MnMOF74 nanocomplex enhanced chemodynamic immunotherapy and effectively inhibited the invasion and metastasis of CT26 tumors."

基金机构："National Natural Science Foundation of China [82171946, 81873901, 82272025]; CQMU Program for Youth Innovation in Future Medicine [W0026]; Basic Research and Frontier Exploration Key Project of Chongqing Science and Technology Commission [cstc2019jcyj-zdxmX0020]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [KR2019G001]; Chongqing Science and Health Joint Medical Research Project-Young and Middle-aged High-level Talent Project [2020GDRC011]; Postdoctoral Science Foundation of China (Pre- Station) [2022TQ0396]"

基金资助正文："Jingxue Wang and Weixi Jiang contributed equally to this work. This work was supported by the National Natural Science Foundation of China (Grant No. 82171946, 81873901, 82272025), CQMU Program for Youth Innovation in Future Medicine(W0026), Basic Research and Frontier Exploration Key Project of Chongqing Science and Technology Commission (Grant No. cstc2019jcyj-zdxmX0020), Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (KR2019G001), and Chongqing Science and Health Joint Medical Research Project-Young and Middle-aged High-level Talent Project (2020GDRC011), the Postdoctoral Science Foundation of China (Pre-Station) (2022TQ0396)."