By integrating bulk and single-cell transcriptomic analyses, we identified a YDC-associated gene signature with strong predictive value, particularly MXD3, DEF6, PLCB2, TBC1D10C, IFNG, CCDC88B, and PLEKHN1, which are important in immune modulation as a potential mechanism underlying poor prognosis in YDC-phenotypic renal cancer patients. Here, DEF6 is linked to renal carcinoma.