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Updated: Feb 18, 2026
Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies
Published on: July 3, 2025
Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC
Vinit Kumar1, Laxminarasimha Donthireddy1, Douglas Marvel1
1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Abstract:
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
Insights
Targeting tumor-associated macrophages (TAM) with CSF1R inhibitors showed limited effects. This study reveals how cancer-associated fibroblasts (CAF) recruit granulocytes, improving anti-tumor therapy when combined with CXCR2 antagonists.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Tumor-associated macrophages (TAM) play a crucial role in tumor progression.
- CSF1R inhibitors targeting TAM are a promising therapeutic strategy but have shown limited anti-tumor efficacy.
- The underlying mechanisms limiting CSF1R inhibitor effectiveness require elucidation.
Purpose of the Study:
- To identify the mechanism limiting the anti-tumor effects of CSF1R inhibitors.
- To investigate the role of carcinoma-associated fibroblasts (CAF) in granulocyte recruitment.
- To explore combination therapies for enhanced anti-tumor activity.
Main Methods:
- Investigated the interaction between tumor cells, CAF, and granulocytes.
- Utilized CSF1R inhibitors and CXCR2 antagonists in preclinical models.
- Analyzed chemokine expression and cellular migration pathways.
Main Results:
- CAF are identified as key sources of chemokines that recruit granulocytes to tumors.
- Tumor-derived CSF1 downregulates granulocyte-specific chemokines in CAF via HDAC2, limiting granulocyte infiltration.
- CSF1R inhibition disrupts this crosstalk, increasing granulocyte recruitment.
- Combination therapy with CSF1R inhibitor and CXCR2 antagonist blocked granulocyte infiltration and demonstrated significant anti-tumor effects.
Conclusions:
- The crosstalk between tumor cells, CAF, and granulocytes is a critical mechanism limiting CSF1R inhibitor efficacy.
- Targeting this crosstalk by combining CSF1R inhibitors with CXCR2 antagonists can overcome therapeutic limitations.
- This combination strategy holds promise for enhanced cancer treatment by modulating the tumor microenvironment.
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