Sun Xiaofan, Zhou Lisha, Wang Yi, Deng Guoliang, Cao Xinran, Ke Bowen, Wu Xiaoqi, Gu Yanhong, Cheng Haibo, Xu Qiang, Du Qianming, Chen Hongqi, Sun Yang
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, 210008, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
J Pharm Anal. 2023 Jul;13(7):726-744. doi: 10.1016/j.jpha.2023.04.013. Epub 2023 Apr 22.
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.
结直肠癌肿瘤通常会营造一种免疫抑制微环境，使其无法对免疫疗法产生反应。大麻二酚（CBD）是一种来自大麻植物的无精神活性天然活性成分，具有多种药理作用，包括神经保护、止吐、抗炎和抗肿瘤活性。本研究旨在通过单细胞RNA测序（scRNA-seq）和单细胞ATAC测序（scATAC-seq）技术阐明CBD的具体抗癌机制。在此，我们报告CBD通过调节抑制性肿瘤微环境（TME）来抑制结直肠癌进展。我们的单细胞转录组和ATAC测序结果表明，CBD在强度和数量上均抑制肿瘤中的M2样巨噬细胞并促进M1样巨噬细胞。此外，CBD显著增强了M1样巨噬细胞与肿瘤细胞之间的相互作用，并恢复了巨噬细胞的内在抗肿瘤特性，从而防止肿瘤进展。从机制上讲，CBD改变了巨噬细胞的代谢模式和相关的抗肿瘤信号通路。我们发现CBD抑制巨噬细胞的替代性激活，并通过抑制磷脂酰肌醇3-激酶-蛋白激酶B信号通路及相关下游靶基因，将代谢过程从氧化磷酸化和脂肪酸氧化转变为糖酵解。此外，CBD介导的巨噬细胞可塑性增强了异种移植小鼠对抗程序性细胞死亡蛋白1（PD-1）免疫疗法的反应。综上所述，我们为CBD的抗肿瘤作用提供了新的见解。
