Single-cell characterization of intra-tumoral heterogeneity and the immunosuppressive microenvironment in uterine serous carcinoma

Uterine serous carcinoma (USC) has a much worse chemotherapy response and prognosis than endometrioid endometrial carcinoma (EEC). A comprehensive understanding of the intra-tumoral heterogeneity and tumor-specific ecosystem of USC is essential for improving diagnosis, treatment, and prognosis. In this study, we performed 5′ single-cell RNA sequencing, along with T-cell receptor and B-cell receptor sequencing, on 16 USC samples and 5 normal endometrial samples. We then integrated data from 15 EEC samples obtained from public databases for comparative analysis. USC malignant cells exhibited novel subclonal genomic complexities and unique transcriptional states, with significantly activated MYC signaling and cell cycle-related pathways. Treatment with the CDK12 inhibitor (CDK12-IN-3) effectively inhibited cell viability and increased the chemotherapy sensitivity of USC cell lines. Additionally, we characterized the stromal niche and immune environment of USC and EEC, finding a higher degree of CD8+ T-cell exhaustion and SPP1+ macrophage infiltration in USC. USC-derived fibroblasts were found to promote malignant cell proliferation through CNTN1-NRCAM, THBS2-CD47, and THBS2-SDC4 interactions. In summary, our study provides a comprehensive single-cell transcriptome analysis of USC and its tumor microenvironment in comparison with EEC, explores intra-tumoral heterogeneity, and identifies CDK12 and CAF-CNTN1 as potential therapeutic targets for USC.