SPP1 + macrophages promote the growth and metastasis of intrahepatic cholangiocarcinoma via OSM and THBS1 signaling

Abstract Background & Aims Tumor-associated macrophages (TAMs) are abundant in intrahepatic cholangiocarcinoma (ICC), correlate with poor prognosis, but their spatiotemporal behavior and non-immune-suppressive roles in ICC progression remain unclear. This study sought to define transcriptional heterogeneity of TAMs and map their interactions with ICC cells that promote malignancy beyond immune suppression. Methods We employed three mouse ICC models, four clinical ICC patient datasets, and three spatial transcriptomic platforms to chart the macrophage landscape over time and space. Cell-cell communication analysis plus phosphoproteomics guided functional validation via TAM-ICC co-culture, cytokine treatment, gene silencing/knockout, orthotopic and metastatic ICC models, and three conditional knockout mice. A prognostic ICC tissue microarray with multiplex immunofluorescence and combinatorial blockade in mice tested the efficacy of dual target inhibition. Results In advanced ICC tissues, an M2-like subset Mφ_SPP1, defined by high expression of SPP1 , VEGFA , ARG1, and GPNMB , emerged as the major macrophage population, correlating with poor prognosis and spatially localizing to the tumor boundary. Further, Mφ_SPP1 drove ICC cell proliferation via the OSM-OSMR-STAT3-CCND1 and promoted invasion through THBS1-CD47-mTOR-DBN1 signalling. OSM and THBS1 were co-elevated in ICC patient samples; dual blockade of both targets in mouse models resulted in superior inhibition of ICC progression. Conclusions Mφ_SPP1 TAMs accumulate at the tumor boundary in late-stage ICC, driving proliferation and invasion via OSM and THBS1 signalling, underscoring the potential of macrophage-targeted therapy in ICC.