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Background:  As the fourth most common malignant tumors in women, uterine corpus endometrial carcinoma (UCEC) requires novel and reliable biomarkers for prognosis prediction to improve the overall survival. Oxidative phosphorylation (OXPHOS) is found to be strongly correlated with the progression of tumor. Here, we aimed to construct an OXPHOS-related and immune microenvironment prognostic signature to stratify UCEC patients for optimization of treatment strategies.   Method:  Prognosis-associated OXPHOS-related differentially expressed genes were identified by multivariable Cox regression from TCGA–UCEC cohort. Based on the candidate genes, an OXPHOS-related prognostic signature was constructed by the train set data and verified by the entire set. When integrated with relevant clinical characteristics, a nomogram was also created for clinical application. Through comparison of tumor microenvironment between different risk groups, the underlying mechanism of the model and the inner correlation between immune microenvironment and energy metabolism were further investigated.   Results:  An OXPHOS-related signature containing ATP5IF1, COX6B1, FOXP3, and NDUFB11 was constructed and had better predictive ability compared with other recently published signatures in UCEC. Patients with lower risk score showed higher immune cell infiltration, higher ESTIMATE score ( p  = 2.808E−18), lower tumor purity ( p  = 2.808E−18), higher immunophenoscores (IPSs) ( p  &amp;lt; 0.05), lower expression of mismatch repair (MMR) proteins ( p  &amp;lt; 0.05), higher microsatellite instability (MSI), lower expression of markers of N6-methyladenosine (m6A) mRNA methylation regulators, higher tumor mutation burden (TMB) ( p  = 1.278E−9), and more sensitivity to immune checkpoint blockade (ICB) ( p  &amp;lt; 0.001) and chemotherapy drugs, thus, possessing improved prognosis.   Conclusion:  An OXPHOS-related and immune microenvironment prognostic signature classifying EC patients into different risk subsets was constructed in our study, which could be used to predict the prognosis of patients and help to select a specific subset of patients who might benefit from immunotherapy and chemotherapy, thus, improving the overall survival rate of UCEC. These findings may contribute to the discovery of novel and robust biomarkers or target therapy in UCEC and give new insights into the molecular mechanism of tumorigenesis and progression of UCEC.

Development of an Oxidative Phosphorylation-Related and Immune Microenvironment Prognostic Signature in Uterine Corpus Endometrial Carcinoma