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. Citation Format: Yuanxing Dong, Xinyue Liu, Xiangqian Zheng. Proline metabolic competition drives CD8+ T cell ferroptosis in BRAF-mutated thyroid cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6994.
Dong et al. (Fri,) studied this question.