{"title":"Applying metabolic control strategies to engineered T cell cancer therapies","authors":"Andrea C. Fox, John Blazeck","doi":"10.1016/j.ymben.2024.10.009","DOIUrl":null,"url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise in improving CAR T cells for the treatment of solid tumors.</div></div>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":"86 ","pages":"Pages 250-261"},"PeriodicalIF":6.8000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Metabolic engineering","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S109671762400137X","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise in improving CAR T cells for the treatment of solid tumors.
嵌合抗原受体(CAR)T 细胞是一种表达合成受体的工程免疫疗法,能识别并杀死癌细胞。尽管 CAR T 细胞在治疗血液肿瘤方面取得了成功,但对实体瘤的疗效有限,部分原因是肿瘤环境中的免疫代谢特征发生了改变,阻碍了 T 细胞的增殖、浸润和抗肿瘤活性。例如,CAR T 细胞必须在肿瘤内争夺必需的营养物质,同时抵御免疫抑制代谢副产物的影响。在这篇综述中,我们将描述实体瘤内导致 CAR T 细胞免疫抑制的代谢特征的改变。我们将讨论关键代谢酶的过度表达如何增强 CAR T 细胞抵抗相应肿瘤代谢变化的能力,甚至将肿瘤的代谢特征恢复到抑制性较弱的状态。此外,代谢重塑与 T 细胞的活性、分化和功能有着内在联系,因此代谢工程策略也能促进建立更有效或更无效的 CAR T 细胞表型。总之,我们将展示应用代谢工程策略如何在改善 CAR T 细胞治疗实体瘤方面大有可为。
期刊介绍:
Metabolic Engineering (MBE) is a journal that focuses on publishing original research papers on the directed modulation of metabolic pathways for metabolite overproduction or the enhancement of cellular properties. It welcomes papers that describe the engineering of native pathways and the synthesis of heterologous pathways to convert microorganisms into microbial cell factories. The journal covers experimental, computational, and modeling approaches for understanding metabolic pathways and manipulating them through genetic, media, or environmental means. Effective exploration of metabolic pathways necessitates the use of molecular biology and biochemistry methods, as well as engineering techniques for modeling and data analysis. MBE serves as a platform for interdisciplinary research in fields such as biochemistry, molecular biology, applied microbiology, cellular physiology, cellular nutrition in health and disease, and biochemical engineering. The journal publishes various types of papers, including original research papers and review papers. It is indexed and abstracted in databases such as Scopus, Embase, EMBiology, Current Contents - Life Sciences and Clinical Medicine, Science Citation Index, PubMed/Medline, CAS and Biotechnology Citation Index.