Single-cell and spatial transcriptome analysis reveals the potential therapeutic targets for testicular sex cord-stromal cell tumor

Abstract Testicular sex cord stromal tumor (TSCST) is a rare testicular tumor with unknown molecular mechanisms, tumor microenvironment (TME) and limited therapeutic options. To define the molecular mechanism and potential targets of TSCST, we combined single-cell RNA sequencing with single-cell nuclear RNA sequencing along with spatial transcriptomics from different TSCST tumor regions. This revealed significantly low expression of immune cell genes in tumor areas, indicating an immune-cold tumor environment and a critical epithelial-mesenchymal transition program during tumorigenesis and disease progression. Also, the study identified high expression levels of the androgen receptor (AR) and related genes in tumor cells, suggesting AR inhibitors as potential therapeutic targets. Furthermore, we identified spatial intra-tumoral heterogeneity, with high senescent characteristics. Finally, the study reports that tumor cells might interact with macrophages, promoting M2 polarization through the APP-CD74 ligand-receptor pair, which has promising therapeutic prospects for this disease. Our data provide comprehensive insights into TSCST, including its cold TME, cellular origins, spatial niches, and cell-cell interactions, highlighting that targeting AR signaling might be a potential therapeutic strategy.