Single-cell analysis identifies endothelial venous thromboembolism signatures as predictors of immunotherapy resistance and survival across cancers.

BACKGROUNDVenous thromboembolism (VTE) is a major complication in cancer patients, yet the transcriptional mechanisms by which tumor-associated endothelial cells drive thrombogenesis and immune evasion remain poorly understood.

OBJECTIVESThis study characterized VTE-related transcriptional signatures in the tumor microenvironment (TME), identified endothelial-specific risk genes, and developed a prognostic model linking hypercoagulation, immune dysfunction, and tumor progression.

METHODSWe systematically analyzed 38 single-cell RNA-sequencing (scRNA-seq) datasets from diverse tumor types to characterize VTE-related gene expression across the TME. Endothelial cells were identified as the primary carriers of the transcriptional signatures of VTE. A VTE score was computed at the single-cell level to describe high-risk endothelial cell subsets. Functional annotation, intercellular communication analysis, and immune profiling were performed to assess the phenotypic and immunologic roles of these genes. Based on bulk RNA-seq datasets from The Cancer Genome Atlas and Gene Expression Omnibus, an endothelial-derived VTE molecular model (Endo.VTM) was constructed. Clustered regularly interspaced short palindromic repeats-associated protein 9 dependency screening was also performed.

RESULTSEndothelial cells with high-VTE scores showed transcriptional programs enriched for coagulation, immune suppression, and altered cell-cell signaling. The Endo.VTM, comprising 12 core genes, demonstrated robust prognostic value across multiple cancer types and was significantly associated with immune checkpoint expression, tumor immune dysfunction, and response to immunotherapy. Clustered regularly interspaced short palindromic repeats-associated protein 9 dependency screening highlights therapeutic vulnerabilities among model genes.

CONCLUSIONWe revealed that endothelial cells serve as central regulators of thrombosis-related transcription in the TME and revealed a novel axis linking VTE, immune evasion, and tumor progression. The Endo.VTM offers a clinically actionable framework for prognostic stratification.