Towards uncovering the roles of intra -tumor heterogeneity in renal carcinoma biology and responses to treatments at a single-cell resolution Intra-tumor heterogeneity (ITH) plays a major role in tumor biology and the effectiveness of targeted therapies. One of the challenges of cancer research today is therefore to identify and characterize the tumor cell subpopulations in order to decipher ITH and better understand its roles in the response to therapies and tumor escape. Here, we developed two research axes using single-cell RNA-sequencing (scRNA-seq) to : 1- characterize the typical pathophysiologic state of clear cell renal cell carcinoma (ccRCC) and its ITH and, 2- assess the impact of anti-cancer drugs on this ITH using 3D organotypic culture model. In the first axis, we processed 5 untreated ccRCC by scRNA-seq and integrated published data of 3 ccRCC tumors and their corresponding healthy tissues. We built a single-cell expression atlas containing 59,242 cells distributed in 33 clusters and corresponding to 14 cell types, including more than 15,000 malignant cells. We observed various degrees of heterogeneity within and across tumors and performed trajectory inference on tumor cells to study the potential molecular stages of carcinogenesis. In the second axis, we developed an integrated protocol enabling us to assess the impacts of up to 6 drugs per tumor, using cell-hashing. We recently processed 4 advanced ccRCC tumors and confirmed the feasibility of the overall approach. Processed data in axes 1 and 2 will soon be available in UncoVer, a web resource developed by our lab and enabling visualization and mining of single-cell omics data in uro-oncology. Overall, this research may contribute to better understand carcinogenesis and tumor escape in ccRCC, promoting new approaches towards personalized medicine in uro-oncology.