Available online 10 October 2025

Author links open overlay panel, , , , , , , , , Abstract

Venous tumor thrombus formation represents a pivotal stage in the metastatic cascade of clear cell renal cell carcinoma (ccRCC). To gain deeper insights into the cellular and molecular landscape underlying this process, we performed comprehensive single-cell RNA sequencing on primary ccRCC tumors and their matched venous tumor thrombi, aiming to systematically characterize the microenvironment of tumor thrombus formation. Our analysis reveals a distinct cellular composition within the tumor thrombus, marked by a significant enrichment of myeloid cells and a relative depletion of T/NK cells, establishing an immunosuppressive milieu at the tumor thrombus site. Notably, we identified a pro-tumorigenic tumor-associated macrophage subpopulation exhibiting M2-like polarization and pro-angiogenic/immunosuppressive characteristics that significantly expanding within the thrombus. Concomitantly, the CD8+ T cell compartment displayed transcriptional signatures indicative of functional exhaustion. Intercellular communication network analysis highlighted the upregulation of adhesion-promoting signaling pathways and context-dependent stromal-immune crosstalk within the thrombus. Furthermore, epithelial cells residing within the tumor thrombus exhibited transcriptional adaptations associated with enhanced migration and survival, alongside increased genomic instability. This study provides a valuable data resource for understanding and targeting the tumor thrombus niche.

Keywords

Clear Cell Renal Cell Carcinoma (ccRCC)

Tumor Thrombus (TT)

Single-Cell RNA Sequencing (scRNA-seq)

Tumor Microenvironment (TME)

Metastasis

Data AvailabilityAll raw data have been submitted to the CNGB (Nucleotide Sequence Archive) (https://db.cngb.cn/gsa/, HRA003584) and also to the GSA (https://ngdc.cncb.ac.cn/gsa/). The human-related data are accessed via an application to the Data Access Committee for research purposes. Potential users will need to complete and be approved for a data access request, and then the raw data can be used for the subjects according to the terms of the consent and the data use limitations.

© 2025 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.