Clear Cell renal carcinoma is the most common kidney malignancy in adults. This tumor shows a high within tumor heterogeneity, and worse patient survival is associated with differences in tumor microenvironments.Clear cell renal carcinoma is the most common kidney malignancy in adults. This tumor shows a high within tumor heterogeneity, and worse patient survival is associated with differences in tumor microenvironments. How the cells in the tumor microenvironment contribute to the tumor advance is not yet fully understood. Our long-term goal is to develop useful biomarkers of ccRCC prognosis that represent a target for personalized therapies for this cancer type. Our overall objectives are 1) to elucidate the diversity of tumor cells and tumor microenvironment cells based on single-cell gene expression patterns, and 2) to determine in subjects with short (<20 months) and long (>60 months) survival which cells and differentially expressed genes are associated with ccRCC survival. The central hypothesis is that specific groups (clusters) of non-tumor cell populations in the tumor microenvironment (immune, endothelial, and stromal cells) promote ccRCC proliferation interacting with tumor cells and affecting patient survival. The rationale for this project is that a determination of clusters of tumoral and non-tumoral cells with differentially expressed genes associated with survival is likely to offer a solid scientific framework to develop additional biomarkers and cancer therapy strategies for ccRCC. Our specific aims will test the following hypotheses: (Aim 1) different numbers/proportions of non-tumor cell lineages/states (distinct clusters of tumor-infiltrating immune cells, endothelial, stromal and other cells) are related to differences in ccRCC survival; (Aim 2) tumor and non-tumor cells will express genes related to vascular and hypoxia VHL pathways, but the gene expression of these and other pathways in non-tumor cells will directly affect ccRCC survival. Upon conclusion, we will have identified and characterized gene expression patterns of specific cells in the tumor microenvironment of ccRCC samples and their relation to ccRCC survival. This contribution is significant since it will establish how interactions between tumor and non-tumoral expressed genes affect patient ccRCC survival after adjusting for age, sex, stage, and treatment. Current studies using single-cell RNAseq have not explored the problem in a population setting, limiting the generalizability of their findings. The proposed research is innovative because, unlike in bulk RNA-seq approaches, we will uncover cell-specific and tumor-specific gene expression mechanisms related to groups of tumor and non-tumor cells that are different between short (<20 months) and long-term (>60 months) survivors.