无结节型甲状腺癌（ATC）是最具侵袭性的肿瘤之一，预后极差。基于ATC中与谷氨酸代谢相关的几个生物特征，我们假设抑制谷氨酰胺代谢可以诱导ATC细胞死亡。然而，抑制谷氨酰胺代谢触发了ATC细胞的生长停滞而与细胞死亡无关，表明存在其他信号通路来避免谷氨酰胺代谢抑制引发的应激。为研究抵抗谷氨酰胺代谢抑制的功能机制，我们进行了mRNA和ATAC测序数据分析，发现谷氨酰胺剥夺增加了ATF4介导的一碳代谢。当我们抑制PHGDH，即一碳代谢的首先限速酶时，在谷氨酰胺代谢抑制下细胞生长停滞通过积累细胞内ROS得到促进。接下来，我们观察到谷氨酰胺和一碳代谢的联合抑制可以增强对ATC患者使用药物的抗癌效果。最后，单细胞RNA测序分析显示一碳代谢在从PTC到ATC的进化过程中得到了加强。综上所述，我们的数据证明一碳代谢在代谢应激中对细胞命运的调控具有潜在作用，并且可以成为增强ATC抗肿瘤效应的治疗靶点。© 2023年。作者。

Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors with an extremely poor prognosis. Based on the several biological features related to glutamine metabolism in ATC, we hypothesized glutaminolysis inhibition induces cell death in ATC cells. However, glutamine metabolism inhibition triggered cell growth arrest independent of cell death in ATC, suggesting that other signaling pathways avoid glutamine metabolism inhibition-induced stress exist. To investigate the functional mechanism against glutamine metabolism inhibition, we conducted mRNA and ATAC-Sequencing data analysis and found that glutamine deprivation increased ATF4-mediated one-carbon metabolism. When we inhibited PHGDH, the first rate-limiting enzyme for one-carbon metabolism, cell growth arrest was promoted upon glutamine metabolism inhibition by accumulating intracellular ROS. We next observed that the co-inhibition of glutamine and one-carbon metabolism could augment the anticancer effects of drugs used in patients with ATC. Finally, single-cell RNA sequencing analysis revealed that one-carbon metabolism was strengthened through the evolutionary process from PTC to ATC. Collectively, our data demonstrate that one-carbon metabolism has a potential role of modulation of cell fate in metabolic stress and can be a therapeutic target for enhancing antitumor effects in ATC.© 2023. The Author(s).