Zou Wenxuan, Han Zitao, Wang Zihan, Liu Qian
Clinical Medicine Department, Xinjiang Medical University, Xinjiang, (New Medical Road Campus), No.393 Xinyi Road, Urumqi, 830054, China.
Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Xinjiang, (Xuelianshan Campus), No.567 Shangde North Road, Urumqi, 830011, China.
J Exp Clin Cancer Res. 2025 Jul 1;44(1):180. doi: 10.1186/s13046-025-03430-7.
Metabolic reprogramming is a hallmark of cancer cells, and the advent of "glutamine addiction" in numerous tumors signifies a pivotal advancement for precision-targeted therapy. This review demonstrates that glutamine metabolism is a pivotal factor in the development of malignant phenotypes in tumors by modulating multifaceted regulatory networks (Hippo/YAP, mTORC1 signaling pathway, and non-coding RNAs). These networks play a crucial role in the reprogramming of glutamine metabolism, which in turn affects various hallmarks of cancer, including cancer cell proliferation, ROS-mediated inhibition of apoptosis, and EMT-associated invasive metastasis. With respect to targeted therapeutic strategies, the focus on key transporters and metabolizing enzymes (ASCT2/GLS1) provides a theoretical foundation for the development of multi-targeted combination therapeutic regimens based on the inhibition of glutamine metabolism. A body of research has demonstrated that the metabolic processes of glutamine regulate a variety of immune system functions, including T cell depletion/activation, the polarization of TAMs, and the function of NK cells. This regulatory relationship, termed the metabolic-immune axis, is a crucial factor in the development of immune escape mechanisms by tumors. The study further suggests that a combination of targeted intervention strategies, involving the modulation of glutamine metabolism, has the potential to reshape the immune microenvironment and enhance the efficacy of CAR-T cell therapy. It is important to note that glutamine metabolism also affects tumor stroma formation by remodeling cancer-associated fibroblasts (CAFs). In response to therapeutic resistance mechanisms, tumor cells form adaptive escapes through ASNS and GAD metabolic branch activation, glucose/lipid metabolic compensation, and ATF4 transcriptional stress networks. This review systematically integrates the critical role of glutamine metabolism in tumor development and therapeutic resistance, providing new perspectives and translational pathways for the development of precision therapeutic strategy selection based on metabolic plasticity modulation.
代谢重编程是癌细胞的一个标志，众多肿瘤中“谷氨酰胺成瘾”现象的出现标志着精准靶向治疗取得了关键进展。本综述表明，谷氨酰胺代谢通过调节多方面的调控网络（Hippo/YAP、mTORC1信号通路和非编码RNA），在肿瘤恶性表型的发展中是一个关键因素。这些网络在谷氨酰胺代谢的重编程中发挥着至关重要的作用，进而影响癌症的各种特征，包括癌细胞增殖、ROS介导的细胞凋亡抑制以及与上皮-间质转化相关的侵袭性转移。关于靶向治疗策略，对关键转运蛋白和代谢酶（ASCT2/GLS1）的关注为基于抑制谷氨酰胺代谢的多靶点联合治疗方案的开发提供了理论基础。大量研究表明，谷氨酰胺的代谢过程调节多种免疫系统功能，包括T细胞耗竭/激活、肿瘤相关巨噬细胞的极化以及自然杀伤细胞的功能。这种调控关系，即代谢-免疫轴，是肿瘤免疫逃逸机制发展的一个关键因素。该研究进一步表明，涉及调节谷氨酰胺代谢的靶向干预策略组合有可能重塑免疫微环境并提高CAR-T细胞治疗的疗效。需要注意的是，谷氨酰胺代谢还通过重塑癌症相关成纤维细胞（CAF）影响肿瘤基质的形成。针对治疗抵抗机制，肿瘤细胞通过ASNS和GAD代谢分支激活、葡萄糖/脂质代谢补偿以及ATF4转录应激网络形成适应性逃逸。本综述系统地整合了谷氨酰胺代谢在肿瘤发展和治疗抵抗中的关键作用，为基于代谢可塑性调节的精准治疗策略选择的开发提供了新的视角和转化途径。
