ObjectiveEndometrial cancer (EC) is one of the most common gynecologic malignancies. The present study aims to identify a metabolism-related biosignature for EC and explore the molecular immune-related mechanisms underlying the tumorigenesis of EC.MethodsTranscriptomics and clinical data of EC were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Common differentially expressed metabolism-related genes were extracted and a risk signature was identified by using the least absolute shrinkage and selection operator (LASSO) regression analysis method. A nomogram integrating the prognostic model and the clinicopathological characteristics was established and validated by a cohort of clinical EC patients. Furthermore, the immune and stromal scores were observed and the infiltration of immune cells in EC cells was analyzed.ResultsSix genes, including CA3, HNMT, PHGDH, CD38, PSAT1, and GPI, were selected for the development of the risk prediction model. The Kaplan-Meier curve indicated that patients in the low-risk group had considerably better overall survival (OS) (P = 7.874e-05). Then a nomogram was constructed and could accurately predict the OS (AUC = 0.827, 0.821, 0.845 at 3-, 5-, and 7-year of OS). External validation with clinical patients showed that patients with low risk scores had a longer OS (p = 0.04). Immune/stromal scores and infiltrating density of six types of immune cells were lower in high-risk group.ConclusionsIn summary, our work provided six potential metabolism-related biomarkers as well as a nomogram for the prognosis of EC patients, and explored the underlying mechanism involved in the progression of EC.