Multi-Omics Analysis Identifies Phosphoglucomutase 2 as a Potential Target to Alleviate Chemoradiotherapy Resistance in Cervical Cancer Cells

Background: As the core treatment for cervical cancer, chemoradiotherapy efficacy is often limited by tumor heterogeneity-driven resistance. During chemoradiotherapy, the tumor microenvironment undergoes dynamic remodeling, with residual malignant cells evolving adaptively. However, the key regulatory genes driving therapeutic resistance remain elusive at single-cell resolution, which hinders the development of novel targeted therapies. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on paired clinical samples from three cervical cancer patients before and after chemoradiotherapy to identify the cellular changes and the molecular mechanisms induced by chemoradiotherapy. Through integrated multi-omics data analysis, non-heterogeneity-dependent genes with prognostic value were identified. Furthermore, the biological function of the candidate gene in chemoradiotherapy-resistant HeLa cells was verified through in vitro functional experiments, including the detection of cell proliferation, migration and invasion abilities. Results: Chemoradiotherapy significantly reprogrammed the cellular composition of the tumor microenvironment (TME) in cervical cancer. Residual malignant cells showed activation of angiogenesis, epithelial-mesenchymal transition, stress-response, and cell-cycle programs. Eight heterogeneity-filtered prognostic genes were identified, and phosphoglucomutase 2 (PGM2) was prioritized because it was upregulated in cervical cancer, enriched in malignant cells, associated with poor prognosis, and supported by independent transcriptomic, spatial, and immunohistochemical evidence. PGM2 knockdown reduced proliferation, migration, and invasion in resistant HeLa cells. Conclusion: PGM2 may contribute to the malignant phenotype of chemoradiotherapy-resistant cervical cancer cells and represents a candidate biomarker and therapeutic target. Further validation in larger clinical cohorts and laboratory work is needed before clinical translation.