文献类型：期刊文献

英文题名：A "Depolarization-Activation" Strategy Targeting Microglia: Cuproptosis-Mediated Immune Re-Sensitization Nanoplatform in Glioma Therapy

作者：Liu, Yi[1];Wu, Yue[2,3];Cao, Ran[2,3];Zhang, Jiting[4];Yuan, Chen[2,3];Xie, Qiang[1];Hu, Jiamin[1];Tabengwa, George Takura[1];Yang, Zijiang[1];Wang, Yunzhi[5];Luo, Rongkui[1,6];Hu, Guangxu[4];Zhu, Wei-Hong[2,3,7];Zhang, Xiaobiao[1];Xu, Yisheng[2,3];Xie, Tao[1]

机构：[1]Fudan Univ, Zhongshan Hosp, Dept Neurosurg, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Sch Chem Engn, State Key Lab Green Chem Engn & Ind Catalysis, Shanghai, Peoples R China;[3]East China Univ Sci & Technol, Ctr Photosensit Chem Engn, Shanghai, Peoples R China;[4]Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China;[5]Fudan Univ, Zhongshan Hosp, Human Phenome Inst, Shanghai, Peoples R China;[6]Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China;[7]East China Univ Sci & Technol, Joint Int Res Lab Precis Chem & Mol Engn, Feringa Nobel Prize Scientist Joint Res Ctr, Sch Chem & Mol Engn,Key Lab Adv Mat,Inst Fine Che, Shanghai, Peoples R China

年份：2026

外文期刊名：ADVANCED FUNCTIONAL MATERIALS

收录：;EI(收录号：20261020218843);WOS:【SCI-EXPANDED(收录号:WOS:001706114900001)】；

基金：National Natural Science Foundation of China (22378126 and 22225805), National Key Research and Development Program (2021YFE0100400), Science and Technology Innovation Plan of Shanghai Science and Technology Commission (22501100500), the Guangxi Science and Technology Innovation Platform Program ("Leitai" Action Plan - Guangxi Laboratory Capacity Building) (LT2504240015), Shanghai Municipal Science and Technology Major Project (22S31902500), Zhongshan Hospital clinical Research Special Project (ZSLCYJ202320, ZSLCYJ202344), Zhongshan Hospital Science and Technology Innovation Fund (2024-ZSCX06).

语种：英文

外文关键词：cuproptosis; glioma; immunotherapy; nanoplatform; tumor-associated microglia/macrophages (TAMs)

摘要：Despite the necessity of repolarizing tumor-associated microglia/macrophages (TAMs) to reverse the highly immunosuppressive microenvironment in gliomas, clinical translation is hindered by tumor heterogeneity and therapeutic dose safety concerns. Here, we develop a "depolarization-activation" strategy: cuproptosis depolarizes TAMs to an "erased" stage regardless of tumor subtypes, leading to a universally enhanced susceptibility to immunoactivating agents. The cuproptosis inducer Elesclomol-Cu (EsCu) and activation agent MK8931 are encapsulated into one nanoplatform with glioma targeting polymers (EsCu/MK@M-P). Sub-lethal level cuproptosis treatment significantly downregulates all polarization markers in TAMs, depolarizing TAMs to an immature state. MK8931 at a low dosage subsequently activates TAMs toward a tumor-killing phenotype, achieving immunotherapeutic efficacy on glioma cells. In vitro and in vivo models, multi-omics analysis, and patient-derived organoids validate broad-spectrum anti-glioma potency and improved biosafety. Therefore, the "depolarization-activation" strategy reveals that sub-lethal hits erase the immunosuppressive property of tumor microenvironment for following immunoactivation, promisingly innovating current cancer immunotherapy strategies.