肿瘤微环境
谷氨酰胺
癌相关成纤维细胞
癌症研究
免疫系统
癌症
肿瘤细胞
肿瘤进展
胰腺癌
化学
生物
细胞生物学
免疫学
生物化学
氨基酸
遗传学
作者
Xiaoyun Li,Sofie Hedlund Møller,Jaeoh Park,Yu‐Ming Chuang,Pei‐Chun Hsueh,Tzu-Hsuan Chang,Kung‐Chi Kao,Hector Gallart-Ayala,Yihao Wang,Jhan-Jie Peng,Alessio Bevilacqua,Yi-Ru Yu,Zhiyu Li,Yann Kieffer,Domitille Peigney,Hugo Croizer,Yingxi Xu,Alfred Zippelius,Isabel C. López‐Mejía,Lluís Fajas
摘要
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.
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