PO.IM02.05 · 免疫学
脯氨酸代谢竞争驱动BRAF突变型甲状腺癌中CD8⁺ T细胞的铁死亡
Proline metabolic competition drives CD8⁺ T cell ferroptosis in BRAF-mutated thyroid cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
脯氨酸代谢中间产物吡咯啉-5-羧酸（P5C）已被认为参与调节T细胞信号传导和效应活性，然而脯氨酸的可用性如何塑造肿瘤-免疫相互作用仍知之甚少。在此，我们证明肿瘤驱动的脯氨酸耗竭在CD8⁺ T细胞中诱导铁死亡，从而促进肿瘤进展。我们鉴定脯氨酸脱氢酶（PRODH）为一个关键的代谢调节因子，其在BRAFV600E突变型甲状腺癌中显著上调，并与增强的肿瘤侵袭性和不良预后密切相关。PRODH升高加速肿瘤细胞中的脯氨酸分解代谢，与CD8⁺ T细胞形成显著的代谢竞争，导致营养剥夺、铁死亡性死亡和抗肿瘤功能受损。从机制上讲，BRAFV600E激活MAPK信号，诱导ERK和JUN依赖性的PRODH转录上调。持续的脯氨酸消耗破坏了“脯氨酸-谷氨酸-GSH”代谢轴，导致氧化还原失衡、ROS过度积累以及铁死亡介导的T细胞功能障碍。值得注意的是，对脯氨酸转运体SLC6A20的药理学抑制可缓解脯氨酸短缺，恢复谷胱甘肽生物合成，并挽救CD8⁺ T细胞的适应性。此外，该代谢环路的功能恢复增强了细胞因子的产生，促进了T细胞在肿瘤微环境中的持久存在，并在体内显著抑制了肿瘤生长。这些发现将BRAFV600E-ERK-PRODH轴确立为脯氨酸代谢重编程的核心驱动因素，其同时增强肿瘤恶性程度并削弱抗肿瘤免疫。此外，我们强调了脯氨酸-谷氨酸-GSH轴在保护CD8⁺ T细胞免于铁死亡中的关键作用，并证明脯氨酸补充或阻断SLC6A20可重建这一保护性通路并增强T细胞介导的抗肿瘤反应，为BRAFV600E驱动的癌症提供了一种有前景的治疗策略。
查看英文原文 English abstract
Proline metabolism intermediate pyrroline-5-carboxylate (P5C) has been implicated in regulating T-cell signaling and effector activity, yet how proline availability shapes tumor-immune interactions remains poorly understood. Here, we demonstrate that tumor-driven proline depletion induces ferroptosis in CD8⁺ T cells and thereby promotes tumor progression. We identify proline dehydrogenase (PRODH) as a key metabolic regulator that is markedly upregulated in BRAFV600E-mutant thyroid cancer and strongly associated with enhanced tumor aggressiveness and poor prognosis. Elevated PRODH accelerates proline catabolism in tumor cells, creating pronounced metabolic competition with CD8⁺ T cells and resulting in nutrient deprivation, ferroptotic death, and impaired antitumor function. Mechanistically, BRAFV600E activates MAPK signaling, which induces ERK- and JUN-dependent transcriptional upregulation of PRODH. Sustained proline consumption disrupts the “proline-glutamate-GSH” metabolic axis, leading to redox imbalance, excessive ROS accumulation, and ferroptosis-mediated T-cell dysfunction. Notably, pharmacological inhibition of the proline transporter SLC6A20 alleviates proline shortage, restores glutathione biosynthesis, and rescues CD8⁺ T-cell fitness. In addition, functional restoration of this metabolic circuit enhances cytokine production, promotes T-cell persistence within the tumor microenvironment, and significantly suppresses tumor growth in vivo. These findings identify the BRAFV600E-ERK-PRODH axis as a central driver of proline metabolic reprogramming that simultaneously enhances tumor malignancy and undermines antitumor immunity. Moreover, we highlight the essential role of the proline-glutamate-GSH axis in protecting CD8⁺ T cells from ferroptosis and demonstrate that proline supplementation or blockade of SLC6A20 can reestablish this protective pathway and reinforce T-cell-mediated antitumor responses, offering a promising therapeutic strategy for BRAFV600E-driven cancers.
利益披露 Disclosure
Y. Dong, None..
X. Liu, None..
X. Zheng, None.