Fibroblast activation protein defines aggressive EMT-associated cancer cell state and prognosis in localized ccRCC

Despite being highly vascularized and immune-rich, the prognostic impact of immune infiltration and tumor microenvironment heterogeneity in localized clear cell renal cell carcinoma (ccRCC) remains unclear. Using 33-marker immunofluorescence imaging, we analyzed spatial distributions in 1,728 tissue cores from 435 localized ccRCC cases. Higher CD45⁺ infiltration correlated with worse survival, establishing CD45⁺ density as a prognostic marker. In CD45 ^high tumors, ccRCC cells losing epithelial markers showed increased expression of mesenchymal markers such as fibroblast activation protein (FAP), secreted protein acidic and rich in cysteine (SPARC), vimentin (VIM), and PD-L1, indicating epithelial-to-mesenchymal transition (EMT). The FAP⁺EMT⁺ state further stratified CD45 ^high patients toward poorer outcomes and was associated with immunosuppressive elements, including M2 macrophages, exhausted and regulatory T cells, and FAP⁺ cancer-associated fibroblasts. Our study identifies high CD45⁺ infiltration and a FAP⁺EMT⁺ cancer cell state as indicators of poor survival in localized ccRCC, highlighting their potential to refine patient stratification and guide immuno-oncology treatment strategies.