Single-Cell Transcriptomics Reveal Distinct Biological and Immunometabolic Landscapes in Renal Medullary Carcinoma Compared to Clear Cell Renal Cell Carcinoma

ABSTRACT: Renal medullary carcinoma (RMC) is a rare, highly aggressive kidney malignancy primarily affecting young individuals of African descent with sickle cell trait. The currently available targeted therapies and immunotherapies approved for clear cell renal cell carcinoma (ccRCC) are ineffective against RMC, highlighting the urgent need for novel treatment approaches specifically tailored to the distinct biological and immune hallmarks of RMC. Here, we performed single-cell RNA-sequencing (scRNA-seq) of tumor samples from five patients with RMC and five patients with ccRCC to define their immunometabolic and transcriptomic landscapes. Differential expression analysis identified ENPP3 and CA9 as distinct cell surface markers upregulated in ccRCC, whereas MUC16, TROP2, and EPCAM were upregulated in RMC tumors cells. RMC displayed a more immunosuppressive tumor microenvironment (TME), with lower infiltration of T and NK cells but an enrichment of immunosuppressive SPP1+ macrophages, contrasting with the more immune-rich TME in ccRCC. Ligand-receptor interaction analyses revealed stronger VEGF-VEGFR signaling in ccRCC and enhanced APP-CD74 signaling in RMC. Nephron anatomy mapping indicated that RMC originates in the loop of Henle, whereas ccRCC arises from proximal tubule cells. We uncovered distinct metabolic reprogramming, with RMC demonstrating higher oxidative phosphorylation (OXPHOS) and lower glycolysis compared to ccRCC. These findings were validated in vitro with RMC cell lines showing elevated oxygen consumption and diminished extracellular acidification compared with ccRCC cell lines. Overall, this study underscores the distinct origins, gene expression patterns, and immunometabolic features of RMC versus ccRCC, offering insights for future tailored therapeutic strategies against RMC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289672 | GEO | 2026/03/28

REPOSITORIES: GEO