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

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

  • J Pharm Anal. 2023 Jul;13(7):726-744. doi: 10.1016/j.jpha.2023.04.013.
Xiaofan Sun 1 2,  Lisha Zhou 2,  Yi Wang 3,  Guoliang Deng 2,  Xinran Cao 2,  Bowen Ke 4,  Xiaoqi Wu 5,  Yanhong Gu 6,  Haibo Cheng 7,  Qiang Xu 2,  Qianming Du 8 9,  Hongqi Chen 10,  Yang Sun 1 2 11
Affiliations

Affiliations

  • 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.
PMID: 37577382 DOI: 10.1016/j.jpha.2023.04.013
Abstract

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.

Keywords

Cannabidiol; Colorectal cancer; Macrophage; Tumor microenvironment; scATAC-seq; scRNA-seq.

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