Cancer-associated fibroblasts (CAFs) support cancer cell metabolism and have been shown to secrete multiple immune factors that can alter the function of immune cells like tumor-associated macrophages (TAMs) to enable tumor growth and survival. Researchers led by Ping-Chih Ho, Xiaoyun Li and Sofie Hedlund Møller of Ludwig Lausanne reported in a July issue of the Journal of Experimental Medicine that palmitic acid, a type of fat secreted by cancer cells, prompts fibroblasts in tumors to ramp up production of the amino acid glutamine. The amino acid switches tumor-associated macrophages (TAMs) into a functional state in which they promote cancer cell proliferation and suppress anti-tumor immune responses. The researchers found that palmitic acid provokes an inflammatory response when it binds its receptor on cancer-associated fibroblasts (CAFs), driving their expression of interleukin-6, which in turn induces heightened expression of glutamine synthetase (GS), an enzyme essential to glutamine production. The researchers showed that knocking out the GS gene in fibroblasts reprograms TAMs and restores anti-tumor immunity, impairing tumor growth in mouse models of melanoma. These findings support the targeting of GS in CAFs as a potential immunotherapy and nominate specific gene expression signatures in the cells as biomarkers for resistance to immunotherapy.
Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages
Journal of Experimental Medicine, 2025 July 16