近年来，靶向谷氨酰胺代谢作为一种有前途的治疗方法受到了重视。谷氨酰胺降解相关酶在调节谷氨酰胺代谢和影响肿瘤免疫微环境（TME）中发挥关键作用。然而，目前有关谷氨酰胺降解酶在肺腺癌（LUAD）中的功能研究十分有限。我们通过体外验证了LUAD细胞对谷氨酰胺的依赖性，然后利用转录组数据鉴定了差异表达基因（DEGs），并利用转录组和单细胞数据分析探索了这些基因在肿瘤免疫微环境中的作用。我们通过在C57BL/6小鼠体内皮下注射刘易斯肺癌细胞来验证候选基因在肿瘤生长和抗肿瘤免疫中的作用。我们的研究发现谷氨酰胺对LUAD细胞的生长至关重要。随后，我们在LUAD患者中鉴定出四个DEGs - 谷氨酸丙酮酸转氨酶1（GPT1）、谷氨酸丙酮酸转氨酶2（GPT2）、谷氨酸草酰乙酸转氨酶1（GOT1）和谷氨酸草酰乙酸转氨酶2（GOT2），它们在肿瘤组织中高度表达，并与免疫抑制性TME密切相关。单细胞测序分析检测到免疫和基质细胞亚群中GOT1和GOT2的高表达水平，而GPT1和GPT2的表达相对较低。基于较低的免疫评分和免疫和基质细胞的较低表达，我们验证了GPT2在体内在调节TME和肿瘤生长方面的作用。抑制GPT2导致肿瘤生长受到抑制，并增加CD4和CD8的表达。此外，GPT2抑制剂与抗程序性细胞死亡配体1联合使用时，可诱导更强的抗肿瘤免疫。本研究首次揭示了谷氨酰胺降解相关酶在TME中的关键作用，并将GPT2确定为抑制LUAD肿瘤生长和改善抗肿瘤免疫反应的有前途的治疗靶点。进一步的研究将需要进一步阐明谷氨酰胺降解相关酶在LUAD中的作用。版权所有©2023 Elsevier Ltd. 保留所有权利。

In recent years, targeting glutamine metabolism has gained attention as a promising therapeutic approach. Glutamine catabolic-related enzymes play a crucial role in modulating glutamine metabolism and influencing immune responses in the tumor immune microenvironment (TME). However, current literature on the function of glutamine catabolic enzymes in lung adenocarcinoma (LUAD) is limited.We validated the glutamine dependency of LUAD cells in vitro, followed by transcriptome data to identify differentially expressed genes (DEGs), with transcriptome and single-cell data analysis utilized to explore the role of such genes within the tumor immune microenvironment. We performed employed subcutaneous injection of lewis lung carcinoma cells in C57BL/6 mice to confirm the role of candidate genes in tumor growth and anti-tumor immunity.Our study revealed that glutamine is essential for the growth of LUAD cells. Subsequently, we identified four DEGs - glutamate pyruvate transaminase 1 (GPT1), glutamate pyruvate transaminase 2 (GPT2), glutamic-oxaloacetic transaminase 1 (GOT1), and glutamic-oxaloacetic transaminase 2 (GOT2) - in LUAD patients, which were highly expressed in tumor tissue and associated with an immunosuppressive TME. Single-cell sequencing analysis detected high expression levels of GOT1 and GOT2 in immune and stromal cell subpopulations, while GPT1 and GPT2 showed relatively lower expression. Based on the lower immune score and lower expression in immune and stromal cells, we validated the role of GPT2 in vivo for modulating the TME and tumor growth. Inhibition of GPT2 resulted in suppressed tumor growth and increased the expression of CD4 and CD8. Additionally, GPT2 inhibitors induced a stronger antitumor immunity when used in combination with anti-programmed cell death ligand 1.This study is the first to show the critical role of glutamine catabolic-related enzymes in the TME, and identified GPT2 as a promising therapeutic target for inhibiting tumor growth and improving anti-tumour immune responses for LUAD. Additional studies will be required to define the roles glutamine catabolic-related enzymes play in LUAD.Copyright © 2023 Elsevier Ltd. All rights reserved.