Tumor cell-derived N-acetyl-aspartyl-glutamate reshapes the tumor microenvironment to facilitate breast cancer metastasis

作     者：Jie Xia Lixing Zhang Wucheng Zhu Juchuanli Tu Xilei Peng Qiaodan Deng Siqin Li Xueyan He Haonan Dong Cuicui Liu Xian Chen Jiahui Xu Wei Ma Yi Xiao Wen Liu Guohong Hu Yi-Zhou Jiang Ceshi Chen Xiu-Wu Bian Zhi-Ming Shao Suling Liu 夏杰;张立行;朱吴骋;屠鞠传礼;彭希磊;邓乔丹;李斯钦;何学艳;董浩楠;刘翠翠;陈贤;许佳慧;马伟;肖毅;刘文;胡国宏;江一舟;陈策实;卞修武;邵志敏;柳素玲

作者机构：Fudan University Shanghai Cancer Center&Institutes of Biomedical SciencesState Key Laboratory of Genetic EngineeringCancer InstitutesDepartment of OncologyKey Laboratory of Breast Cancer in ShanghaiThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Key Laboratory of Radiation OncologyThe International Co-laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyShanghai Medical CollegeFudan UniversityShanghai 200032China Jinfeng LaboratoryChongqing 401329China Jiangsu Key Lab of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjing 211166China Key Laboratory of Breast Cancer in ShanghaiDepartment of Breast SurgeryFudan University Shanghai Cancer Center and Cancer InstituteShanghai Medical CollegeFudan UniversityShanghai 200032China Key Laboratory of Breast Cancer in ShanghaiDepartment of Breast SurgeryFudan University Shanghai Cancer CenterShanghai 200032China Department of OncologyShanghai Medical CollegeFudan UniversityShanghai 200032China Precision Cancer Medical CenterFudan University Shanghai Cancer CenterShanghai 201315China School of Pharmaceutical SciencesFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200032China Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan ProvinceKunming Institute of ZoologyKunming 650201China Academy of Biomedical Engineering&The Third Affiliated HospitalKunming Medical UniversityKunming 650500China Institute of Pathology and Southwest Cancer CentreSouthwest HospitalThe Third Military Medical UniversityChongqing 400038China 

出 版 物：《Science Bulletin》 (科学通报(英文版))

年 卷 期：2025年第70卷第7期

页      面：1126-1138页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Key Research and Development Program of China(2023YFC2506400 and 2020YFA0112300) the National Natural Science Foundation of China(82230103,82073267,W2431054,81930075,and 82372689) “Ten Thousand Plan”-National High-Level Talents Special Support Plan(WR-YK5202101) Program for Outstanding Leading Talents in Shanghai,Program for Outstanding Medical Academic Leader in Shanghai(2019LJ04) Program of Shanghai Academic/Technology Research Leader(20XD1400700) 

主　　题：Breast cancer metastasis NAAG PMN-MDSC RIMKLB NMDAR 

摘      要：Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity.N-acetyl-aspartyl-glutamate(NAAG)has been extensively studied in neurological disorders;however,its potential role in restricting anti-tumor immunity has not been ***,we demonstrated that NAAG or its synthetase RimK-like family member B(RIMKLB)significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs),which in turn promoted breast cancer growth and ***,NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor(NR2B-NMDAR)-dependent p38-NOTCH1 axis,and subsequently stimulating tumor cell migration and invasion,as well as inducing PMN-MDSC differentiation and *** mouse models,RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor *** analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC ***,our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.