Tumor cell FAP orchestrates EMT and immune suppression in aggressive localized ccRCC

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• High immune cell infiltration in clear cell renal cell carcinoma (ccRCC) paradoxically correlates with poor prognosis.
• Mechanisms linking tumor-immune interactions to ccRCC invasion and recurrence are poorly understood.

Purpose of the Study:

• To identify spatial features of tumor, immune, and stromal cells defining aggressive ccRCC phenotypes.
• To investigate the role of fibroblast activation protein (FAP) in ccRCC progression.

Main Methods:

• Multiplex immunofluorescence with a 33-marker panel on 1,728 tissue cores from 435 ccRCC patients.
• Single-cell analysis of immune, stromal, endothelial, and epithelial cells within spatial context.
• Inclusion of tumor centers, invasive borders, and adjacent benign tissues.

Main Results:

• A distinct aggressive ccRCC subtype identified by fibroblast activation protein (FAP) expression on tumor epithelial cells.
• Tumor-cell FAP associated with epithelial-to-mesenchymal transition (EMT)-like state and profound immunosuppression (Tregs, exhausted CD8+ T cells, M2 macrophages).
• Tumor-cell FAP promoted invasion and independently predicted poorer recurrence-free survival (RFS), outperforming PD-L1.

Conclusions:

• Tumor epithelial FAP expression defines an aggressive, immune-rich ccRCC subtype integrating EMT and immunosuppression.
• Tumor-cell FAP serves as a potential biomarker for risk stratification and targeted therapies in ccRCC.
• FAPI-PET imaging and FAP-directed therapies are promising translational avenues.