Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target. [Display omitted] • We present a robust pipeline for scRNA-seq analysis by protein activity inference • Our pipeline identifies a C1Q+TREM2+APOE+ macrophage population enriched in ccRCC • Protein activity signature of these cells is prognostic of post-surgical recurrence • C1Q+ Macrophage association with recurrence is validated by immunohistochemistry Analysis of the tumor microenvironment using tumor and tumor-adjacent tissue of treatment-naive clear cell renal carcinoma resections from patients by combining single-cell sequencing and single-cell protein activity uncovers a tumor-specific infiltrating macrophage subpopulation associated with disease recurrence. [ABSTRACT FROM AUTHOR]