Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers

Sep 21, 2026

Uploaded by Miles

Tumor-associated macrophages support tumor growth and contribute to treatment resistance. CSF-1R blockade is a promising strategy, yet its effects on human macrophage metabolism remain insufficiently defined. Using RNA sequencing and metabolomics, the study characterizes macrophage reprogramming under a CSF-1R kinase inhibitor, linking receptor inhibition to impaired cholesterol and fatty acid pathways and reduced hypoxia-driven dihydropyrimidine dehydrogenase expression.

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CategoryResearch & Report

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Open access Original research Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers Khaldoun Gharzeddine,1 Cristina Gonzalez Prieto ,1,2 Marie Malier,1 Clara Hennot,1 Renata Grespan,1 Yoshiki Yamaryo-Botté,1 Cyrille Y Botté,1 Fabienne Thomas,3 Marie-Hélène Laverriere,1,4 Edouard Girard,5 Gael Roth,1,6 Arnaud Millet 1,6 To cite: Gharzeddine K, Gonzalez Prieto C, Malier M, et al. Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers. Journal for ImmunoTherapy of Cancer 2024;12:e009602 . doi:10.1136/jitc-2024-009602 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2024-009602](jitc-2024-009602)) . Accepted 09 September 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. For numbered affiliations see end of article. Correspondence to Dr Arnaud Millet; [arnaud.millet@inserm.fr](arnaud.millet@inserm.fr) ABSTRACT Background Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colonystimulating factor 1 receptor (CSF-1R) receptor is oneof the most promising ones. Here, we characterize the resulting state of human macrophages exposed to a CSF- 1R kinase inhibitor. Methods Using RNA sequencing and metabolomics approach, we characterize the reprogramming of human monocyte-derived macrophages under CSF-1R targeting. Results We find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF- 1R receptor leads to a downregulation of the expression of sterol regulatory element-binding protein 2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of extracellular signalregulated kinase 1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of hypoxic induced factor 2 alpha in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer. Conclusions These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages and its potential to reverse macrophage-mediated chemoresistance in colorectal tumors. BACKGROUND A large body of work has been reported providing compelling evidence that tumorassociated macrophages (TAMs) are involved in tumor growth, treatment resistance and metastasis.1 2 Indeed, TAMs are associated with poor prognosis in the vast majority of solid tumors.3 Consequently, great efforts WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Colony-stimulating factor 1 receptor (CSF-1R) targeting is a promising strategy to modulate the innate immune response in cancer. However, the effect of this targeting on human macrophage phenotype isnot fully understood.
WHAT THIS STUDY ADDS | | --- | | ⇒ In this study, we report that CSF-1R targeting affects the metabolic state of tumor-associated macrophages notably the cholesterol synthesis pathway, the fatty acid synthesis pathway and the hypoxic induced factor 2a-mediated response involving dihydropyrimidine dehydrogenase expression.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY | ⇒ CSF-1R targeting appears to be a promising strategy to circumvent the macrophage-mediated chemoresistance to 5-fluorouracil in colorectal cancer. h

FAQs

What role do tumor-associated macrophages play in cancer treatment outcomes?

Tumor-associated macrophages are involved in tumor growth and treatment resistance, and they are linked to poor prognosis in most solid tumors.

How does CSF-1R targeting influence human macrophage metabolism?

CSF-1R inhibition impairs cholesterol synthesis and fatty acid metabolism and reduces hypoxia-driven dihydropyrimidine dehydrogenase expression.

Why is dihydropyrimidine dehydrogenase important for chemotherapy response in colorectal cancer?

The study links reduced dihydropyrimidine dehydrogenase expression to restoration of sensitivity to 5-fluorouracil in colorectal cancer, reversing macrophage-mediated chemoresistance.

Sep 21, 2026

Uploaded by Miles