Abstract
Previous bulk RNA sequencing or whole genome sequencing on clear cell renal cell carcinoma (ccRCC) subtyping mainly focused on ccRCC cell origin or the complex tumor microenvironment (TME). Based on the single-cell RNA sequencing (scRNA-seq) data of 11 primary ccRCC specimens, cancer stem-cell-like subsets could be differentiated into five trajectories, whereby we further classified ccRCC cells into three groups with diverse molecular features. These three ccRCC subgroups showed significantly different outcomes and potential targets to tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). Tumor cells in three differentiation directions exhibited distinct interactions with other subsets in the ccRCC niches. The subtyping model was examined through immunohistochemistry staining in our ccRCC cohort and validated the same classification effect as the public patients. All these findings help gain a deeper understanding about the pathogenesis of ccRCC and provide useful clues for optimizing therapeutic schemes based on the molecular subtype analysis.