Dual functional nanoplatforms potentiate osteosarcoma immunotherapy via microenvironment modulation  

作　　者：Shunyi Lu Yuqi Yang Zhuorun Song Jie Cao Zhihui Han Linfu Chen Yunfei He Jiayi Wang Yun Teng Zengli Zhang Jun Zou Jun Ge Huilin Yang Liang Cheng 

机构地区：[1]Department of Orthopedic Surgery,The First Affiliated Hospital of Soochow University,Suzhou 215123,China [2]Institute of Functional Nano&Soft Materials(FUNSOM),Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices,Soochow University,Suzhou 215123,China [3]Soochow University Institues for Translational Medicine,The First Affiliated Hospital of Soochow University,Suzhou 215123,China [4]Department of Orthopedic Surgery,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai 200233,China [5]Department of Environmental Health School of Public Health,Soochow University,Suzhou 215123,China

出　　处：《National Science Review》2025年第3期363-378,共16页国家科学评论(英文版)

基　　金：suppor ted by the National Key Re-search and Development Program of China(2022YFB3804600);the National Natural Science Foundation of China(52472288,82172506 and 82030068);the Collaborative Innovation Center of Suzhou Nano Science and Technology,the Suzhou Key Laboratory of Nanotechnology and Biomedicine,the Science and Technology Development Fund,the Macao SAR(0118/2023/RIA2,0064/2024/AMJ and 0016/2024/RIA1);the Jiangsu Natural Science Fund for Distinguished Young Scholars(BK20211544);the Overseas Expertise Introduction Project for Discipline Innovation(111 Project);the Joint International Research Laboratory of Carbon-Based Functional Materials and Devices,the Jiangsu Funding Program for Excellent Postdoctoral Talent(2024ZB491);the China Postdoctoral Science Foundation(2024M752333);the Natural Science Foundation BoXi Cultivation Program Project of the First Affiliated Hospital of Soochow University(BXQN2023013).

摘　　要：Osteosarcoma(OS),a highly aggressive bone tumor,presents significant challenges in terms of effective treatment.We identified that cellular autophagy was impaired within OS by comparing clinical OS samples through bioinformatic analyses and further validated the inhibition of mitochondrial autophagy in OS at the transcriptomic level.Based on this finding,we investigated the therapeutic potential of a dual functional metal nanoplatform(MnS_(x))to facilitate a transition from the protective effect of low-level autophagy in OS to the killing effect of high-level autophagy in OS.MnS_(x)facilitated intracellular H_(2)S generation via endocytosis,leading to the S-sulfhydration of ubiquitin-specific peptidase 8(USP8)and subsequent promotion of mitochondrial autophagy in vitro.Additionally,MnS_(x)activated the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway,further enhancing the cellular autophagic response and accelerating tumor cell death.Moreover,it was demonstrated in vivo that MnS_(x),on the one hand,mediated the activation of tumor autophagy by USP8 via intracellular H_(2)S,while Mn^(2+)promoted the maturation of dendritic cells,activated cytotoxic T lymphocytes and contributed to tumor eradication.Such tumor killing could be suppressed by the autophagy inhibitor chloroquine.Importantly,synergistic combination therapy with immune checkpoint inhibitors showed promise for achieving complete remission of OS.This study highlights the potential of MnS_(x)as a dual-functional therapeutic platform for OS treatment and offers novel directions for future research in this field.

关 键 词：OSTEOSARCOMA metal nanoplatform MnSx H2 S gas therapy AUTOPHAGY IMMUNOTHERAPY 

分 类 号：R738.1[医药卫生—肿瘤]