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<p>Clear cell renal cell carcinoma (ccRCC) is a common and aggressive kidney cancer with poor prognosis due to its frequent late-stage diagnosis and immunosuppressive tumor microenvironment (TME). While ccRCC is responsive to immunotherapies, treatment resistance remains a major challenge, underscoring the need for new therapeutic targets. We performed integrated single-cell and bulk transcriptomic analysis of ccRCC and normal kidney tissues to characterize the immune landscape and identify key ligand–receptor interactions within the TME. Gene expression and survival data were analyzed using public datasets. Functional validation was conducted using a ccRCC xenograft mouse model treated with the CSF1R inhibitor Sotuletinib. Single-cell analysis revealed that enhanced communication between M2-like macrophages and malignant epithelial cells in ccRCC, with the CSF1-CSF1R signaling axis playing a central role. Elevated expression of CSF1 and CSF1R correlated with poor patient prognosis and increased macrophage infiltration. In vivo inhibition of CSF1R reduced tumor growth, decreased Ki67+ cell proliferation, and suppressed CD163+ M2 macrophage polarization. This study suggests a potential role of CSF1-CSF1R-mediated macrophage-epithelial crosstalk in promoting immunosuppressive TME and tumor progression in ccRCC. Importantly, CellChat-based predictions represent potential, rather than definitive, ligand–receptor interactions, and thus require further mechanistic validation. Targeting CSF1R may offer a promising strategy to modulate the immune landscape and improve therapeutic outcomes in ccRCC.</p>

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CSF1-CSF1R signaling mediates tumor cell-macrophage crosstalk and prognosis in ccRCC

  • 期刊论文

  • 发表日期：

    2025年11月27日

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  • Xing Li,
  • Yanjun Li,
  • Lei Zhang,
  • Libin Zhou,
  • Huimin Long

摘要

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive kidney cancer with poor prognosis due to its frequent late-stage diagnosis and immunosuppressive tumor microenvironment (TME). While ccRCC is responsive to immunotherapies, treatment resistance remains a major challenge, underscoring the need for new therapeutic targets. We performed integrated single-cell and bulk transcriptomic analysis of ccRCC and normal kidney tissues to characterize the immune landscape and identify key ligand–receptor interactions within the TME. Gene expression and survival data were analyzed using public datasets. Functional validation was conducted using a ccRCC xenograft mouse model treated with the CSF1R inhibitor Sotuletinib. Single-cell analysis revealed that enhanced communication between M2-like macrophages and malignant epithelial cells in ccRCC, with the CSF1-CSF1R signaling axis playing a central role. Elevated expression of CSF1 and CSF1R correlated with poor patient prognosis and increased macrophage infiltration. In vivo inhibition of CSF1R reduced tumor growth, decreased Ki67+ cell proliferation, and suppressed CD163+ M2 macrophage polarization. This study suggests a potential role of CSF1-CSF1R-mediated macrophage-epithelial crosstalk in promoting immunosuppressive TME and tumor progression in ccRCC. Importantly, CellChat-based predictions represent potential, rather than definitive, ligand–receptor interactions, and thus require further mechanistic validation. Targeting CSF1R may offer a promising strategy to modulate the immune landscape and improve therapeutic outcomes in ccRCC.