Molecular Mechanisms and Senescence Signatures in Cervical Squamous Cell Carcinoma: Insights from Transcriptomic and Single-cell Analyses

INTRODUCTION: Cervical squamous cell carcinoma remains a major medical challenge worldwide, particularly in low-developed regions. This study integrated bulk transcriptomic (GSE63514) and single-cell RNA sequencing data (GSE168652) to investigate how senescencerelated mechanisms contribute to CESC progression. By leveraging this multi-omics integration, the study provides unprecedented resolution into cell-type-specific senescence programmes and their associated intercellular communication networks that drive CESC pathogenesis. METHODS: Differential expression analysis was performed on bulk data, followed by functional enrichment analysis. Single-cell analysis characterised senescence signals across cell types and intercellular communications. Network pharmacology identified potential therapeutic agents targeting senescence pathways. RESULTS: We identified 1,319 upregulated and 913 downregulated genes in tumours compared to normal tissues. Functional enrichment analysis revealed pathways involved in cell cycle arrest (CDKN2A/p16INK4A), DNA repair (DNA2), and extracellular matrix remodelling (MMP12, CTHRC1). CDKN2A mediated growth suppression via p53/Rb signalling, while SASP components (AIM2, CXCL9) and APOC1-associated metabolic dysregulation shaped an immunosuppressive microenvironment. Single-cell analysis showed strong senescence signals in epithelial cells and macrophages, involving CDKN2A and APOC1. MIF and MDK signalling between these cells appeared to support immune evasion and angiogenesis. Network pharmacology indicated possible therapies, including CDK4/6 inhibitors, a strategy supported by findings in related HPV-associated malignancies, as well as MMP12 inhibitors and combinations of PARP inhibitors with immune checkpoint blockade. DISCUSSION: These findings provide a more detailed picture of senescence in CESC, with tumour-suppressive effects through CDKN2A and pro-tumorigenic effects via SASP components and APOC1. Cell-cell interactions involving MIF and MDK may drive immune evasion. CONCLUSION: This study demonstrated both the promoting and suppressive roles of senescence in CESC and identified potential therapeutic targets, offering hope for improved outcomes in high-risk patients from low-resource regions.