Single-nucleus RNA sequencing reveals heterogenous microenvironments and specific drug response between cervical squamous cell carcinoma and adenocarcinoma

BACKGROUND: Cervical squamous cell carcinoma (CSCC) and adenocarcinoma (CAde) are two major pathological types of cervical cancer (CC), but their high-resolution heterogeneity of tumor and immune microenvironment remains elusive. METHODS: Here, we performed single-nucleus RNA sequencing (snRNA-seq) from five CSCC and three CAde samples, and systematically outlined their specific transcriptome atlas. FINDINGS: We found CD8(+) T cells in CSCC were more cytotoxic but lower exhausted compared to those in CAde, and phagocytic MRC1(+) macrophages were specifically enriched in CSCC. Interestingly, we discovered that pro-tumoral cancer-associated myofibroblasts (myoCAFs) and cancer-associated vascular-fibroblasts (vCAFs) were more abundant in CSCC, and further verified their pro-metastatic roles in vitro. Furthermore, we also identified some specific chemotherapy drugs for CSCC (Dasatinib and Doramapimod) and CAde (Pyrimethamine and Lapatinib) by revealing their heterogeneity in transcriptomic profiles of malignant epithelial cells, and further verified their specific sensitivity in cell lines and constructed CC-derived organoids. Cell–cell communication networks revealed that the pathways of NRG1-ERBB2, and FN1-ITAG3 were specific for CAde and CSCC, respectively, which may partly explain the specificities of identified chemotherapy drugs. INTERPRETATION: Our study described the immune heterogeneity and specific cellular interactions between CSCC and CAde, which could provide insights for uncovering pathogenesis and designing personalized treatment. FUNDINGS: 10.13039/501100012166National Key R&D Program of China (2021YFC2701201), 10.13039/501100001809National Natural Science Foundation of China (82072895, 82141106, 82103134, 81903114).