Mitochondria-targeted atovaquone promotes anti-lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti-tumor immune cells.
Mitochondria-targeted atovaquone promotes anti-lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti-tumor immune cells.
复制标题
线粒体靶向的阿托伐醌通过重塑肿瘤微环境和增强抗肿瘤免疫细胞的能量代谢来促进抗肺癌免疫。
DOI：
10.1002/cac2.12500
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
You,Ming
中科院分区：
文献类型：
--
作者：
Xiong,Donghai;Yin,Zheng;Huang,Mofei;Wang,Yian;Hardy,Micael;Kalyanaraman,Balaraman;Wong,StephenT;You,Ming
Dear Editor, Atovaquone (ATO), a mitochondrial inhibitor, has anti-cancer effects [1]. Based on ATO, we developed mitochondria-targeted atovaquone (Mito-ATO) that had even stronger anti-tumor efficacy than ATO [2]. We synthesized Mito-ATO by attaching the bulky triphenylphosphonium (TPP) group to ATO via a ten-carbon alkyl chain (Supplementary file of methods; Supplementary Figure S1). To assess the effects of Mito-ATO on tumor microenvironment, we conducted single-cell RNA-sequencing (scRNA-seq) on treated immune cells from mice having lung tumors either treated with or without Mito-ATO. Seurat was used for clustering and annotation of CD45+ immune cells [3]. The detected lymphoid cell populations were CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), gamma-delta T (Tgd) cells, B cells, and natural killer (NK) cells; and the myeloid cells identified were macrophages, neutrophils, plasmacytoid dendriticList of abbreviations: Aco1, aconitase 1; Aco2, aconitase 2; ATO, atovaquone; CD4IL2RAHI, IL2RA-high CD4+ Treg; CD4IL2RALO, IL2RA-low CD4+ Treg; CD4T_Cytotoxic, cytotoxic CD4+ T cells; CD4T_Exhausted, exhausted CD4+ T cells; CD8T_EffectorMemory, effector memory like CD8+ T cells; CD8T_Exhausted, exhausted CD8+ T cells; CD8T_MemoryLike, memory like CD8+ T cells; CD8T_Naive, naive CD8+ T cells; cDC, conventional dendritic cells; FDR, false discovery rate; Glud1, glutamate dehydrogenase 1; G-MDSC, granulocytic myeloid-derived suppressor cells; Got1, glutamic-oxaloacetic transaminase 1; Idh3a, isocitrate dehydrogenase 3 alpha; Idh3b, isocitrate dehydrogenase 3 beta; Idh3g, isocitrate dehydrogenase 3 gamma; Ldha, lactate dehydrogenase A; Mdh1, malate dehydrogenase 1; Mdh2, malate dehydrogenase 2; Mito-ATO, mitochondria-targeted atovaquone; Mpc2, mitochondrial pyruvate carrier 2; NES, normalized enrichment score; NK, natural killer cells; OXPHOS, oxidative phosphorylation; pDC, plasmacytoid dendritic cells; Pkm, pyruvate kinase; ROS, reactive oxygen species; TCA, tricarboxylic acid; Tgd, gammadelta T cells; TILPRED, tumor-infiltrating CD8+ lymphocytes states predictor; TPP, triphenylphosphonium; Tregs, regulatory T cells.
