Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages
Xiaoyun Li # 1 2, Sofie Hedlund Møller # 1 2, Jaeoh Park 1 2, Yu-Ming Chuang 1 2, Pei-Chun Hsueh 1 2, Tzu-Hsuan Chang 1 2, Kung-Chi Kao 1 2, Hector Gallart-Ayala 3, Yi-Hao Wang 1 2, Jhan-Jie Peng 1 2 4 5, Alessio Bevilacqua 1 2, Yi-Ru Yu 1 2, Zhiyu Li 1 2 6, Yann Kieffer 7, Domitille Peigney 7, Hugo Croizer 7, Yingxi Xu 1 2, Alfred Zippelius 8 9, Isabel C Lopez-Mejia 10, Lluis Fajas 10, Fatima Mechta-Grigoriou 7, Julijana Ivanisevic 3, Zhengtao Xiao 11, Ming-Chih Ho 12, Ying-Chun Shen 13 14, Ping-Chih Ho 1 2 15
. 2025 Sep 1;222(9):e20241426.
doi: 10.1084/jem.20241426. Epub 2025 Jul 16.
- PMID: 40668214
- DOI: 10.1084/jem.20241426
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.