Page 137 - 南京医科大学自然版

第46卷第10期 南京医科大学学报（自然科学版）
2026年10月 Journal of Nanjing Medical University（Natural Sciences） ·1567 ·

·综 述·

谷氨酰胺代谢和肿瘤耐药机制研究进展

陈奕文 ，张静静 ，张雄飞 3*
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南京中医药大学第一临床医学院，江苏 南京 210023；南京医科大学第一附属医院普外科，江苏 南京 210029；南京中
1 2 3
医药大学医学院生物化学与分子生物学系，江苏 南京 210023

［摘 要］ 恶性肿瘤细胞表现出显著的代谢重塑特征，具体表现在对谷氨酰胺（glutamine，Gln）等代谢底物的摄取能力显著增
强。这种代谢改变不仅为肿瘤细胞内异常活跃的糖酵解途径和线粒体氧化磷酸化过程提供必要的代谢前体物质，同时通过干
扰糖类、脂类以及氨基酸代谢的动态平衡，直接导致肿瘤组织对化学治疗药物产生耐药性。然而，对于肿瘤细胞如何调控Gln
代谢可塑性以逃避肿瘤药物的杀伤，目前尚没有系统性阐述，同时也缺乏针对Gln代谢在不同癌症类型、不同微环境中作用差
异性的梳理以及临床转化失败原因的深入分析。文章总结了Gln代谢在肿瘤耐药形成过程中的关键调控作用及其耐药机制，
首次提出“Gln代谢⁃微环境⁃免疫逃逸”三维耐药模型，并指出当前靶向治疗的三大瓶颈，以期为改善恶性肿瘤耐药性的临床治
疗策略提供理论依据和方法学参考。
［关键词］ 谷氨酰胺；代谢重编程；肿瘤微环境；耐药；谷氨酰胺转运体；蛋白质翻译后修饰；表观遗传调控；DNA损伤修复
［中图分类号］ R730.5 ［文献标志码］ A ［文章编号］ 1007⁃4368（2026）10⁃1567⁃17
doi：10.7655/NYDXBNSN260141

Research progress on glutamine metabolism and tumor drug resistance mechanisms
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Chen Yiwen ，Zhang Jingjing ，Zhang Xiongfei 3*
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1 School of Clinical Medicine，Nanjing University of Chinese Medicine，Nanjing 210023；Department of General
Surgery，the First Affiliated Hospital of Nanjing Medical University，Nanjing 210029；Department of Biochemistry
3
and Molecular Biology，Medical College，Nanjing University of Chinese Medicine，Nanjing 210023，China

［Abstract］ Malignant tumor cells undergo profound metabolic reprogramming，manifested by a markedly enhanced capacity for the
uptake of specific metabolic substrates，most notably glutamine（Gln）. This metabolic adaptation not only provides essential precursors
to support aberrantly active glycolysis and mitochondrial oxidative phosphorylation but also disrupts the homeostatic balance of
carbohydrate，lipid，and amino acid metabolism，thereby directly contributing to the adaptive resistance of tumor tissues to
chemotherapeutic agents. Despite its significance，a systematic understanding of how tumor cells modulate Gln metabolic plasticity to
evade drug⁃induced cytotoxicity remains elusive. Furthermore，there is a notable lack of in⁃depth analyses addressing the context⁃
dependent variability of Gln metabolism across different cancer types and microenvironments，as well as the underlying causes of the
failures in clinical translation. This review systematically delineates the key regulatory roles and mechanistic pathways through which
Gln metabolism drives the acquisition of drug resistance in malignant tumors. For the first time，we propose a three ⁃ dimensional
resistance framework ⁃ termed the“Gln metabolism ⁃ microenvironment ⁃ immune evasion”model and identify three major bottlenecks
inherent in current targeted therapeutic strategies. Collectively，this review aims to establish a theoretical foundation and provide
methodological insights to inform and improve clinical treatment strategies for drug⁃resistant malignant tumors.
［Key words］ glutamine；metabolic reprogramming；tumor microenvironment；drug resistance；glutamine transporters；protein post⁃
translational modifications；epigenetic regulation；DNA damage repair
［J Nanjing Med Univ，2026，46（10）：1567⁃1583］

［基金项目］ 伊犁州临床医学研究院面上项目（yl2023ms12）
通信作者（Corresponding author），E⁃mail：zhangxiongfei@njucm.edu.cn（ORCID：0000⁃0002⁃2962⁃3645）
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