Unveiling Gamma-Interferon-Inducible Lysosomal Thiol Reductase (IFI30) as a Regulator of Macrophage Polarization and Prognostic Biomarker by Multi-Transcriptome Analysis in Cervical Cancer

Abstract

Cervical cancer remains a significant challenge to global health, necessitating the development of reliable clinical prognostic models to predict patient survival outcomes with accuracy. This study aims to develop an mRNA signature model based on tumor immune infiltration characteristics of cervical cancer. By employing RNA sequencing technologies at both tissue and single-cell resolutions, a survival predictive gene signature was constructed for cervical cancer through the application of machine learning methods. To further validate the key prognostic genes identified in the prognostic signature, we performed additional experiments, including tissue microarray (TMA) analysis and in vitro assays. Our developed signature model comprised nine genes, which ranks at the top tier when compared to previously published mRNA signature models. Gamma-interferon-inducible lysosomal thiol reductase (IFI30) emerged as a critical prognostic marker, validated externally through immunohistochemistry (IHC) and multiplex immunohistochemistry staining (mIHC) on cervical cancer TMAs. Notably, IFI30 exhibited pronounced expression in macrophages compared to other cell types within the tumor microenvironment (TME). We further investigated the potential role of IFI30 in regulating macrophage polarization. Specifically, a reduced expression of IFI30 in macrophages co-cultured with HeLa cells induced a polarization transition from the M2 to the M1 phenotype. In conclusion, we have successfully established a prognostic model on the basis of tumor immune infiltration characteristic of cervical cancer, highlighting IFI30 as a pivotal prognostic marker potentially involved in macrophage polarization. Future investigation is required to explore the underlying mechanisms for the advancement of therapeutic strategies in cervical cancer.