Coordination of Single-cell and Bulk RNA Sequencing to Construct a Cuproptosis-related Gene Prognostic Index for Endometrial Cancer Prognosis, Immune Microenvironment Infiltration, and Immunotherapy Treatment Options

Background: This study aims to identify molecular subtypes and develop a cuproptosis-related gene prognostic index (CRGPI) for endometrial cancer (EC), in addition to outlining the immune features and the efficacy of immune checkpoint inhibitor (ICI) therapy in CRGPI-defined groups of EC. Methods: Between malignant and normal cells distinguished from single-cell RNA sequencing data GSE154763 dataset, the difference in KEGG pathways and cuproptosis-related gene (CRG) scores was intensively investigated. On the basis of TCGA dataset (n=492), CRGs were used to identify two distinct molecular subtypes. Using the Cox regression method, a CRGPI was constructed and externally validated with the IMvigor210 dataset (n=348) and GSE78220. Then, the molecular and immune characteristics and the efficacy of ICI therapy in subgroups defined by CRGPI were investigated. Results: Compared to normal cells, the expression of the TCA cycle and CRGs genes was significantly higher in malignant cells. The CRGPI was established on the premise of ATF5, FBXO46, P2RX4, SMARCD3, DAPK3, and C1orf53. Comprehensive results demonstrated a correlation between a low CRGPI score and better overall survival, younger age, early stage, immune cells and functions activation, high tumor mutation burden and high microsatellite instability, as well as better benefit from ICI therapy, and its significance for forecasting immunotherapeutic effects was verified as well (IMvigor210 cohort: HR, 1.358; 95% CI, 1.047, 1.761; p=0.02; GSE78220 cohort: HR, HR = 3.857, 95% CI, 1.009, 14.74; p=0.034). CRGPI anticipated the immunotherapy medication. Conclusions: CRGPI is a prospective biomarker to estimate the prognosis, immune and molecular characteristics, and treatment benefit of immunotherapy in EC.