近日，南京医科大学吕凌及其小组的最新研究揭示了肿瘤产生的氨被调节性T细胞代谢，进一步阻碍抗肿瘤免疫。相关论文于2025年12月24日发表在《细胞》杂志上。
以空间代谢组学和转录组学为主题，研究团队发现人类肝细胞癌存在代谢异质性亚区，其特征是谷氨酰胺水解和氨含量高，Tregs经常存在，但CD8+和CD4+效应T细胞死亡。该课题组发现Tregs通过上调精氨酸琥珀酸裂解酶（ASL）来调节尿素循环解毒；同时，氨也通过FOXP3转录因子调控的精胺合成酶（SMS）转化为精胺。X射线晶体学证实精胺与PPARγ之间存在直接相互作用，从而全面调节多种线粒体复合物蛋白的转录，从而增强Tregs的氧化磷酸化和免疫抑制。在临床上，抗PD-1治疗垂死的肿瘤细胞，通过脱氨作用释放氨，从而增强Treg功能，导致免疫治疗耐药性。靶向氨生成抑制Tregs是一种潜在的抗肿瘤免疫治疗策略。
研究人员表示，调节性T细胞（Tregs）适应苛刻的肿瘤代谢微环境以抑制抗肿瘤免疫的机制仍不清楚。
附：英文原文
Title: Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity
Author: Jian Gu, Yu Li, Qiuyang Chen, Ziyan Song, Qufei Qian, Yuan Liang, Tianning Huang, Lei Qiao, Xiangyu Li, Miao Yu, Mu Liu, Jinren Zhou, Qing Shao, Xiaozhang Xu, Robert Zeiser, Ling Lu
Issue&Volume: 2025-12-24
Abstract: Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8+ and CD4+ effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.
DOI: 10.1016/j.cell.2025.11.034
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01369-8