Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer  

作　　者：Xiaofan Sun Lisha Zhou Yi Wang Guoliang Deng Xinran Cao Bowen Ke Xiaoqi Wu Yanhong Gu Haibo Cheng Qiang Xu Qianming Du Hongqi Chen Yang Sun 

机构地区：[1]Department of Rheumatology and Immunology,Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School,Nanjing University,Nanjing,210008,China [2]State Key Laboratory of Pharmaceutical Biotechnology,School of Life Sciences,Nanjing University,Nanjing,210023,China [3]Colon and Rectal Surgery,Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine,Nanjing,210001,China [4]Laboratory of Anesthesia and Critical Care Medicine,Department of Anesthesiology,Translational Neuroscience Center,West China Hospital and State Key Laboratory of Biotherapy,Sichuan University,Chengdu,610044,China [5]Genergy Bio-technology(Shanghai)Co.,Ltd,Shanghai,200241,China [6]The First Affiliated Hospital of Nanjing Medical University,Jiangsu Province Hospital,Nanjing,210029,China [7]Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor,The First Clinical College of Nanjing University of Chinese Medicine,Nanjing,210023,China [8]General Clinical Research Center,Nanjing First Hospital,Nanjing Medical University,Nanjing,210006,China [9]School of Basic Medicine&Clinical Pharmacy,China Pharmaceutical University,Nanjing,210009,China [10]Department of General Surgery,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai,200030,China [11]Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,Xuzhou Medical University,Xuzhou,Jiangsu,221004,China

出　　处：《Journal of Pharmaceutical Analysis》2023年第7期726-744,共19页药物分析学报（英文版）

基　　金：supported by the National Key Research and Development Plan,China(Grant No.:2022YFC3500202);the Natural Science Foundation of China(Grant Nos.:82172558,and 82205024);the Scientific and Technological Innovation Action Plan of Natural Science Foundation Project of Shanghai,China(Grant No.:22ZR1447400);the Scientific and Technological Innovation Action Plan,China(Grant No.:22ZR1447400);the Fundamental Research Funds for the Central Universities,China(Grant Nos.:020814380179,020814380174);the Distinguished Young Scholars of Nanjing,China(Grant No.:JQX20008);the School of Life Science(NJU)-Sipimo Joint Funds and Mountain Climbing Talents Project of Nanjing University,China(Grant No.:2015018).

摘　　要：Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

关 键 词：scRNA-seq scATAC-seq CANNABIDIOL Colorectal cancer Tumor microenvironment MACROPHAGE 

分 类 号：R737.9[医药卫生—肿瘤]