Immune cell clustering identifies a CD163⁺/CSF1R⁺ macrophage and neutrophil-enriched phenotype with distinct biological signatures and poor prognosis in angiosarcoma

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The tumor immune microenvironment (TIME) influences tumor biology and therapeutic response, yet its composition and clinical relevance in angiosarcoma, an ultrarare and aggressive sarcoma with a dismal prognosis, remain poorly defined. To address this gap, we comprehensively profiled the TIME of 63 angiosarcomas (AS), including primary cutaneous, secondary, and visceral subtypes, with a focus on colony-stimulating factor 1 receptor (CSF1R)-expressing tumor-associated macrophages (TAMs). Using conventional and multiplex immunohistochemistry with quantitative analysis, we found that CD68⁺/CD163⁺ (M2-like) TAMs predominated across all AS subtypes. The enrichment of CD68⁺/CD163⁺/CSF1R⁺ TAMs was strongly associated with shorter overall and disease-free survival. Unsupervised clustering revealed three immune phenotypes, among which a CSF1R-high macrophage/neutrophil-enriched cluster was independently associated with poor overall survival. Proteomic profiling of these high-risk angiosarcomas within this cluster demonstrated upregulation of oxidative phosphorylation, angiogenesis, and neutrophil-associated pathways, alongside downregulation of extracellular matrix organization, indicating a metabolically distinct and immunologically myeloid-driven tumor state and immune phenotype. These findings identify CSF1R⁺ macrophage enrichment as a defining feature of high-risk angiosarcoma and suggest that improved biological understanding of the CSF1R axis may allow additional immunomodulatory therapeutic strategies in this rare and aggressive malignancy.

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