Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
Journal
The Journal of experimental medicine
Journal Volume
222
Journal Issue
9
ISSN
1540-9538
Date Issued
2025-09-01
Author(s)
Li, Xiaoyun
Møller, Sofie Hedlund
Park, Jaeoh
Chuang, Yu-Ming
Hsueh, Pei-Chun
Chang, Tzu-Hsuan
Kao, Kung-Chi
Gallart-Ayala, Hector
Wang, Yi-Hao
Peng, Jhan-Jie
Bevilacqua, Alessio
Yu, Yi-Ru
Li, Zhiyu
Kieffer, Yann
Peigney, Domitille
Croizer, Hugo
Xu, Yingxi
Zippelius, Alfred
Lopez-Mejia, Isabel C
Fajas, Lluis
Mechta-Grigoriou, Fatima
Ivanisevic, Julijana
Xiao, Zhengtao
Ho, Ping-Chih
Abstract
In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving TLR4, Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.
SDGs
Type
journal article