单细胞分析揭示出，大麻二酚通过抑制巨噬细胞的可选激活，重新调控肿瘤微环境，并且在结肠癌中与抗PD-1具有协同作用。
Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer.
发表日期：2023 Jul
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
来源：
Cell Death & Disease
摘要：
结直肠肿瘤往往形成免疫抑制的微环境，阻碍其对免疫治疗的反应。大麻植物的非精神活性天然活性成分大麻二酚（Cannabidiol，CBD）具有多种药理作用，包括神经保护、抗恶心、抗炎和抗肿瘤活性。本研究旨在通过单细胞RNA测序（single-cell RNA sequencing，scRNA-seq）和单细胞ATAC测序（single-cell ATAC sequencing，scATAC-seq）技术阐明CBD的特异性抗癌机制。在这里，我们报告了CBD通过调节抑制性肿瘤微环境（tumor microenvironment，TME）来抑制结直肠癌的进展。我们的单细胞转录组和ATAC测序结果显示，CBD不仅在数量上抑制了M2样巨噬细胞，还促进了M1样巨噬细胞的形成。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，并恢复了巨噬细胞固有的抗肿瘤特性，从而阻止了肿瘤的进展。在机制上，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抑制了巨噬细胞的替代激活，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提高了转基因小鼠对抗程序性细胞死亡蛋白-1（programmed cell death protein-1，PD-1）免疫治疗的反应。综上所述，我们对CBD的抗肿瘤效应提供了新的见解。© 2023 The Author(s).
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.© 2023 The Author(s).