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A Ludwig Most cancers Analysis research has recognized a posh chain of molecular chatter by which most cancers cells, exploiting atypical metabolic processes, program one set of noncancerous cells to control one other set of such cells to help their development and survival.
Researchers led by Ping-Chih Ho, Xiaoyun Li and Sofie Hedlund Møller of the Lausanne Department of the Ludwig Institute for Most cancers Analysis have found that sure fats molecules secreted by most cancers cells immediate fibroblasts—workhorse cells usually coopted by tumors—to ramp up manufacturing of the amino acid glutamine.
They report within the Journal of Experimental Drugs that this amino acid switches immune cells generally known as macrophages right into a purposeful state through which they promote most cancers 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,” mentioned 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 rising appreciation for the subtle roles seemingly humdrum cells like fibroblasts—which, amongst different issues, crank out the fibrous stuff of tissues—play in tumor biology. Recruited and reprogrammed by most cancers cells, cancer-associated fibroblasts (CAFs) have been proven to secrete a number of immune components that may alter the operate of immune cells like tumor-associated macrophages (TAMs) to allow tumor development and survival. CAFs additionally help most cancers cell metabolism, offering vitamins important to producing the vitality and mobile constructing blocks that maintain their fast proliferation.
In exploring how the metabolic profile of tumors shapes their immune landscapes, the Ludwig Lausanne researchers discovered glutamine to be notably plentiful in melanoma tumors. This was of fast curiosity to them as a result of the amino acid is thought to modulate the operate of TAMs. Additional research revealed that glutamine synthetase (GS), an enzyme important to its biosynthesis, is expressed at particularly excessive ranges by CAFs in these tumors.
Møller, Li, Ho and colleagues found that palmitic acid (similar because the fats in palm oil) produced by melanoma cells engages receptors on the floor of CAFs that set off their expression of genes concerned in irritation. A type of genes is for interleukin-6 (IL-6), an element that acts on the infected CAFs themselves to ramp up their expression of GS. This in flip elevates glutamine ranges within 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,” mentioned 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 of their paper the biochemical signaling cascades in CAFs that result in inflammatory responses, such because the manufacturing of IL-6 and GS. Additionally they present that knocking out the gene for GS in fibroblasts reprograms TAMs and restores anti-tumor immunity, impairing tumor development in mouse fashions of melanoma.
Notably, the researchers additionally present that CAFs expressing genes required for glutamine synthesis are carefully related to pro-tumorigenic TAMs in genomic datasets from breast most cancers sufferers.
“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,” mentioned Li. With additional research and affirmation of our findings, such markers might assist clinicians establish tumors which have an immunosuppressive microenvironment and are probably to withstand immunotherapy.”
Extra data:
Xiaoyun Li et al, Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages, Journal of Experimental Drugs (2025). DOI: 10.1084/jem.20241426
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Ludwig Most cancers Analysis
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How metabolic chatter between cells undermines anti-tumor immunity (2025, July 17)
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