JULY 16, 2025, NEW YORK - A Ludwig Cancer Research study has identified a complex chain of molecular chatter by which cancer cells, exploiting ordinary metabolic processes, program one set of noncancerous cells to manipulate another set of such cells to support their growth and survival.
Researchers led by Ping-Chih Ho, Xiaoyun Li and Sofie Hedlund Møller of the Lausanne Branch of the Ludwig Institute for Cancer Research have discovered that certain fat molecules secreted by cancer cells prompt fibroblasts-workhorse cells often coopted by tumors-to ramp up production of the amino acid glutamine. They report in the Journal of Experimental Medicine that this amino acid switches immune cells known as macrophages into a functional state in which they promote cancer cell proliferation and suppress anti-tumor immune responses.
"Our findings offer new insights into the complexity of the tumor microenvironment and illustrate a previously unknown mechanism by which cancer cells sculpt their metabolic environment to serve multiple needs," said Ho. "They also suggest potential strategies to reprogram that microenvironment to support anti-tumor immune responses and improve the efficacy of immunotherapy."
Researchers have a growing appreciation for the sophisticated roles seemingly humdrum cells like fibroblasts-which, among other things, crank out the fibrous stuff of tissues-play in tumor biology. Recruited and reprogrammed by cancer cells, cancer-associated fibroblasts (CAFs) 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. CAFs also support cancer cell metabolism, providing nutrients essential to generating the energy and cellular building blocks that sustain their rapid proliferation.
In exploring how the metabolic profile of tumors shapes their immune landscapes, the Ludwig Lausanne researchers found glutamine to be particularly abundant in melanoma tumors. This was of immediate interest to them because the amino acid is known to modulate the function of TAMs. Further study revealed that glutamine synthetase (GS), an enzyme essential to its biosynthesis, is expressed at especially high levels by CAFs in these tumors.
Møller, Li, Ho and colleagues discovered that palmitic acid (same as the fat in palm oil) produced by melanoma cells engages receptors on the surface of CAFs that trigger their expression of genes involved in inflammation. One of those genes is for interleukin-6 (IL-6), a factor that acts on the inflamed CAFs themselves to ramp up their expression of GS. This in turn elevates glutamine levels in the tumor microenvironment, pushing TAMs into an immunosuppressive and pro-tumorigenic state.
"Our findings reveal a new way that cancer hijacks surrounding cells to protect itself and grow," said Møller. "Glutamine metabolism is already being studied as a potential target for cancer treatment due to its effects on both cancer cells and immune cells. Our findings suggest that targeting glutamine production in fibroblasts may contribute to the benefits of such therapies."
The researchers describe in their paper the biochemical signaling cascades in CAFs that lead to inflammatory responses, such as the production of IL-6 and GS. They also show that knocking out the gene for GS in fibroblasts reprograms TAMs and restores anti-tumor immunity, impairing tumor growth in mouse models of melanoma.
Notably, the researchers also show that CAFs expressing genes required for glutamine synthesis are closely associated with pro-tumorigenic TAMs in genomic datasets from breast cancer patients.
"Components of the signaling pathway that we found to be triggered by palmitic acid-such as glutamine synthetase and proteins involved in the inflammatory CAF responses-could be useful as biomarkers," said Li. With further study and confirmation of our findings, such markers could help clinicians identify tumors that have an immunosuppressive microenvironment and are likely to resist immunotherapy."
This study was funded by Ludwig Cancer Research, the Cancer Research Institute, the Swiss National Science Foundation, Helmut Horten Stiftung and the Melanoma Research Alliance.
Ping-Chih Ho is a member of the Lausanne Branch of the Ludwig Institute for Cancer Research and a full professor at the University of Lausanne.
