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

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.