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

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.