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

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.

NEDD8-conjugating enzyme E2 UBE2F confers radiation resistance by protecting lung cancer cells from apoptosis

Lung cancer,which is exacerbated by environmental pollution and tobacco use,has become the most common cause of cancer-related deaths worldwide,with a five-year overall survival rate of only 19%(Siegel et al.,2020;Yang et al.,2020;Yu and Li,2020).Nearly 85%of lung cancers are non-small cell lung cancers,of which lung adenocarcinoma is the most common subtype accounting for 50%of non-small cell lung cancer cases.At present,radiotherapy is the primary therapeutic modality for lung cancer at different stages,with significant prolongation of survival time(Hirsch et al.,2017;Bai et al.,2019;Shi et al.,2020).

Targeting protein phosphatases for the treatment of inflammation-related diseases:From signaling to therapy

Inflammation is the common pathological basis of autoimmune diseases,metabolic diseases,malignant tumors,and other major chronic diseases.Inflammation plays an important role in tissue homeostasis.On one hand,inflammation can sense changes in the tissue environment,induce imbalance of tissue homeostasis,and cause tissue damage.On the other hand,inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis.These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases.Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases,which have a crucial role in inflammatory homeostasis.The mechanisms by which many kinases resolve inflammation have been well reviewed,whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking.The molecular knowledge of protein phosphatases,and especially the unique biochemical traits of each family member,will be of critical importance for developing drugs that target phosphatases.Here,we provide a comprehensive summary of the structure,the“double-edged sword”function,and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases,as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials.We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammationrelated diseases,with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.