An Immune Exclusion Index Identifies T/NK Cell Effector Deficiency and a Barrier-Like Microenvironmental State in MMRp/MSS Endometrial Cancer

Mismatch repair-proficient or microsatellite stable (MMRp/MSS) endometrial cancer derives limited benefit from immune checkpoint inhibitor monotherapy, and immune exclusion may reflect both barrier-like tumor-stromal programs and insufficient T cell/natural killer cell (T/NK-cell) effector activity. We integrated The Cancer Genome Atlas uterine corpus endometrial carcinoma (TCGA-UCEC), Clinical Proteomic Tumor Analysis Consortium (CPTAC)-UCEC, GSE17025, GSE21882, and GSE251923 to derive and evaluate an immune exclusion index (IEI) in candidate MMRp/MSS tumors. IEI was derived from a 112-gene biologically constrained candidate pool using Cox elastic-net modeling in the TCGA candidate MMRp/MSS cohort (243 tumors, 39 death events). The weighted 9-gene IEI showed apparent association with poor overall survival in the same TCGA cohort (unadjusted hazard ratio [HR] = 5.06, 95% confidence interval [CI] 2.80–9.14, p = 7.77e-08; adjusted HR = 2.00, 95% CI 1.37–2.93, p = 3.62e-04). Median stratification gave HR = 8.15. Gene Expression Omnibus cohorts supported the adverse phenotype direction but not independent MMRp/MSS survival validation; CPTAC and GSE251923 supported RNA-protein and spot-level marker consistency. IEI provides an interpretable framework for candidate T/NK-low, barrier-like microenvironmental states.