This study is the first report demonstrating a novel mechanism by which CD70 promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis, at least in part, through suppression of NF1 and subsequent activation of the Ras/ERK signaling pathway, which may further drive EMT-related features and enhance tumor metastatic potential. These insights provide a mechanistic rationale for targeting CD70, either alone or in combination with inhibitors of the Ras/ERK pathway or modulators of EMT, to impede metastasis in patients with advanced ccRCC.