A P4HA2 hypoxia signature derived from single cell atlas stratifies conserved subtypes with prognostic significance in cervical squamous cell carcinoma.

BACKGROUND: Cervical cancer, especially cervical squamous cell carcinoma (CSCC), is a major public health issue in low- and middle-income countries, with advanced recurrence and metastasis linked to poor prognosis. It shows significant intra-tumoral phenotypic heterogeneity and plasticity. METHODS: We analyzed the single-cell RNA sequencing data of cervical squamous cell carcinoma available in the Gene Expression Database (GEO) and identified the tumor cell subtype exhibiting hypoxic characteristics. We extracted differentially expressed genes (HRDEGs) between this hypoxia-related cluster and other tumor cells. Based on the CSCC bulk RNA sequencing data from the Cancer Genome Atlas (TCGA), this subtype was confirmed to be closely associated with poor prognosis in CSCC.101 combinations consisting of 10 machine learning models were used for screening prognostic biomarkers in HRDEGs, and a hypoxia signature was established by multivariate COX regression. RESULTS: The hypoxia signature, validated using external GEO datasets, was significantly correlated with tumor invasiveness. Further analysis demonstrated that immune infiltration and responses to both chemotherapy and immunotherapy are associated with the hypoxia signature. In addition, the key gene P4HA2 in the hypoxia signature has been demonstrated to be involved in the regulation of malignant phenotypes of tumor cells and the regulation of HIF-1α stability. CONCLUSIONS: Overall, this hypoxia signature is a promising independent prognostic factor, provides potential biomarkers for the prognosis of CSCC and may guide future investigations into patient stratification. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15597-z.