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

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.