Page 145 - 南京医科大学自然版

第46卷第10期 陈奕文，张静静，张雄飞. 谷氨酰胺代谢和肿瘤耐药机制研究进展［J］.
2026年10月 南京医科大学学报（自然科学版），2026，46（10）：1567-1583 ·1575 ·

观遗传机制，能够导致肿瘤细胞对化疗药物耐药。 通过增强核苷酸代谢，补充因5⁃FU抑制而减少的核
3.6 Gln代谢与DNA损伤修复 苷酸池，从而维持 DNA 合成和修复的正常进行，这
肿瘤细胞能够通过提升核苷酸代谢水平以及 种代谢重编程使得肿瘤细胞能够抵抗 5⁃FU 的毒性
DNA 损伤修复能力，抵御化疗药物或放疗引发的 作用，进而发展耐药性 ［50］ 。顺铂耐药细胞对营养匮
DNA损伤，进而促使耐药性形成。核苷酸代谢是细 乏的敏感性与其对 Gln 的显著依赖性密切相关，即
胞合成 DNA 和 RNA 的基础，其代谢过程涉及多种 在营养匮乏条件下，这些细胞更容易死亡，原因在
酶和代谢途径。5⁃氟尿嘧啶（5⁃fluorouracil，5⁃FU）是 于它们高度依赖Gln以维持生存和生长。而在某些
一种经典的抗代谢药物，主要用于治疗结直肠癌等 顺铂耐药肿瘤细胞中，Gln 主要通过参与核苷酸的
肿瘤，在某些结直肠癌细胞中，Gln代谢增强通过提 生物合成途径发挥作用，而非参与TCA循环或氧化
供更多的代谢中间体，支持核苷酸代谢的进行，并 还原反应。Obrist等 ［51］ 研究表明，补充Gln可以挽救

Resistance to
glutaminease
inhibitors（e.g.，CB⁃839）
Cystine
NK Cell
Gln
Gln
SLC1A5
M2⁃TAM
Glutamine Cysteine GSH
competition
SLC1A5
GLS1
Gln CDC42
Reduced Activate Microvesicles
GLS1
IFN⁃γ and
Glutamine
immune NF⁃κB p65
depletion Glu IL⁃6
suppression
IQGAP1
GSH
Activate
TCA STAT3
cycle
GLS1
ROS Ras pathway
Mitochondrial CAF
balence Gln
ATP PYCR1
OXPHOS
T cell
Metabolic
CD39
A2A Lactate
coupling
recceptor CD73
Inhibit Oxidative
T cell phosphorylation
Collagen
activation Adenosine
Drugs
and
proliferation
ECM stiffening
（drug barrier）
Tumor cells competitively uptake Gln from the microenvironment through high expression of SLC1A5 and GLS1，leading to local Gln depletion and
establishing a Gln competition microenvironment. This nutrient scarcity forces metabolic reprogramming in T cells and natural killer cells，resulting in
reduced IFN⁃γ secretion and subsequent immune suppression. Concurrently，tumor cells activate NF⁃κB p65 via CDC42 and interact with IQGAP1 to
drive the secretion of GLS1⁃containing microvesicles，which induce M2⁃type tumor⁃associated macrophage（TAM）polarization. M2⁃TAM secretes IL⁃6
to activate STAT3 signaling in tumor cells，further upregulating GLS1 expression and glutathione synthesis，thereby forming a positive feedback loop. In
addition，TAM converts ATP into adenosine via CD39 and CD73；adenosine then binds to the A2A receptor on the surface of T cells，inhibiting T cell
activation and proliferation. Cancer⁃associated fibroblasts form a metabolic coupling with tumor cells，secreting Gln and lactate that are taken up by
tumor cells. This enhances mitochondrial oxidative phosphorylation，maintains reactive oxygen species homeostasis，and confers resistance to
glutaminase inhibitors（e.g.，CB⁃839）. Activation of the Ras signaling pathway in CAF increases Gln synthesis. Furthermore，CAF promotes collagen
secretion and extracellular matrix stiffening through upregulation of PYCR1，thereby forming a drug barrier that impedes drug penetration and ultimately
leads to multidrug resistance.
图4 肿瘤微环境中谷氨酰胺代谢介导的耐药机制
Figure 4 Mechanisms of glutamine metabolism⁃mediated drug resistance in the tumor microenvironment