Macrophages display spatiotemporal specificity in intrahepatic cholangiocarcinoma and drive tumour progression via OSM and THBS1

Wang, T.; Long, R.; Cheng, Z.; Zhang, M.; Wei, B.; Lyu, C.; Zhang, C.; Tang, G.; Li, Z.; Li, L.; Li, Y.; Zhu, X.; Shi, C.; Yang, K.; Xu, C.

doi:10.1101/2025.10.02.679723

bioRxiv · 10.1101/2025.10.02.679723

Macrophages display spatiotemporal specificity in intrahepatic cholangiocarcinoma and drive tumour progression via OSM and THBS1

Wang, T.·Long, R.·Cheng, Z.·Zhang, M.·Wei, B.·Lyu, C.·Zhang, C.·Tang, G.·Li, Z.·Li, L.·Li, Y.·Zhu, X.·Shi, C.·Yang, K.·Xu, C.

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Abstract

Tumor-associated macrophages (TAMs) are abundant in intrahepatic cholangiocarcinoma (ICC) and correlate with poor prognosis, but their non-immunosuppressive roles remain unclear. This study aimed to define TAM transcriptional heterogeneity and map their interactions with ICC cells that promote malignancy beyond immune suppression. Single-cell and spatial transcriptome analysis with mouse and human ICC tissues revealed a TAM subpopulation, designated M{varphi}_VEGFA, that emerged as the major macrophage population from the intermediate stage of ICC development onward. Data from Gene Expression Omnibus (GEO) and spatial transcriptome indicate that M{varphi}_VEGFA was associated with poor prognosis and spatially localized to the ICC cells. Cell co-culture and cell-cell communication analyses revealed that M{varphi}_VEGFA promoted ICC cell proliferation via secreted OSM and downstream OSMR-STAT3-CCND1 axis, and enhanced ICC cell invasion through THBS1 and downstream CD47-mTOR/DBN1 signaling. Critically, multiplex immunofluorescence with human ICC tissue microarray indicated that OSM and THBS1 were co-elevated in human ICCs, and dual blockade of both targets inhibited ICC progression in mouse models. This study uncovers the direct and critical roles of M{varphi}_VEGFA in driving ICC progression with paracrine signaling and further highlights the potential of targeting macrophages in ICC treatment.

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Wang, T., Long, R., Cheng, Z., Zhang, M., Wei, B., Lyu, C., Zhang, C., Tang, G., Li, Z., Li, L., Li, Y., Zhu, X., Shi, C., Yang, K., Xu, C.. 2025-10-04. Macrophages display spatiotemporal specificity in intrahepatic cholangiocarcinoma and drive tumour progression via OSM and THBS1. https://doi.org/10.1101/2025.10.02.679723

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