Glut1 and MCT4 cooperatively promote ccRCC cell proliferation and are associated with glycolytic reprogramming and immune-related alterations.

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by glycolytic reprogramming and a lactate-rich tumor microenvironment. We integrated multi-omics, single-cell, tissue microarray, and in vitro analyses to investigate the roles of Glut1 and MCT4 in ccRCC. Both transporters were upregulated at the mRNA and protein levels, enriched in tumor epithelial cells, and located within a glycolysis-associated co-expression module. Elevated MCT4 expression and combined Glut1/MCT4 dysregulation were associated with poor overall survival, while a glycolysis-related random forest model improved prognostic prediction. Functionally, Glut1 and MCT4 exhibited reciprocal expression changes and promoted cell proliferation and cell-cycle progression. Combined knockdown produced a greater inhibitory effect than either individual knockdown in both 786-O and Caki-1 cells. Computational analyses further associated Glut1/MCT4 expression with immune-related features and predicted immunotherapy response, whereas metabolomics revealed elevated lactate and ribose 5-phosphate levels. Collectively, these findings identify a coordinated Glut1-MCT4 axis associated with proliferative, metabolic, prognostic, and immune-related features in ccRCC, although further mechanistic and in vivo validation is required.