Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada.
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
Nat Metab. 2024 Mar;6(3):396-408. doi: 10.1038/s42255-024-00976-2. Epub 2024 Feb 22.
The broad effectiveness of T cell-based therapy for treating solid tumour cancers remains limited. This is partly due to the growing appreciation that immune cells must inhabit and traverse a metabolically demanding tumour environment. Accordingly, recent efforts have centred on using genome-editing technologies to augment T cell-mediated cytotoxicity by manipulating specific metabolic genes. However, solid tumours exhibit numerous characteristics restricting immune cell-mediated cytotoxicity, implying a need for metabolic engineering at the pathway level rather than single gene targets. This emerging concept has yet to be put into clinical practice as many questions concerning the complex interplay between metabolic networks and T cell function remain unsolved. This Perspective will highlight key foundational studies that examine the relevant metabolic pathways required for effective T cell cytotoxicity and persistence in the human tumour microenvironment, feasible strategies for metabolic engineering to increase the efficiency of chimeric antigen receptor T cell-based approaches, and the challenges lying ahead for clinical implementation.
T 细胞为基础的疗法治疗实体肿瘤癌症的广泛有效性仍然有限。这部分是由于人们越来越认识到，免疫细胞必须居住并穿过代谢要求高的肿瘤环境。因此，最近的努力集中在使用基因组编辑技术通过操纵特定的代谢基因来增强 T 细胞介导的细胞毒性。然而，实体瘤表现出许多限制免疫细胞介导的细胞毒性的特征，这意味着需要在途径水平而不是单个基因靶点上进行代谢工程。由于许多关于代谢网络和 T 细胞功能之间复杂相互作用的问题仍未解决，这一新兴概念尚未付诸临床实践。本观点将重点介绍关键的基础研究，这些研究检查了在人类肿瘤微环境中有效 T 细胞细胞毒性和持久性所需的相关代谢途径、增加嵌合抗原受体 T 细胞为基础的方法效率的代谢工程的可行策略，以及临床实施面临的挑战。
