Heterogeneity in Clinicopathological and PD-L1 Expression Profiles Across Mismatch Repair Protein Deficiency Patterns in Endometrial Carcinoma

Objectives: This study aimed to investigate the relationships among mismatch repair (MMR) protein status, clinicopathological characteristics, and Programmed Death-Ligand 1 (PD-L1) expression in endometrial cancer, focusing specifically on heterogeneity within MMR-deficient (MMRd) tumors defined by distinct protein loss patterns. Methods: This retrospective study enrolled 675 patients with surgically confirmed endometrial cancer at a tertiary medical group between January 2017 and June 2025. Patients were stratified according to specific MMR protein loss patterns. Clinicopathological parameters, the International Federation of Gynecology and Obstetrics (FIGO) stage, and PD-L1 combined positive score were compared across groups. Results: The cohort comprised 502 MMR-proficient (MMRp) and 173 MMR-deficient (MMRd) patients. Based on their specific MMR protein loss patterns, the MMRd cases were further stratified into three subgroups: MutLαcomplex loss (MLH1 ± PMS2, n = 105), MutSαcomplex loss (MSH2 ± MSH6, n = 60), and combined MutSα/MutLαcomplex loss (n = 8). Compared with MMRp tumors, MMRd tumors exhibited significantly lower BMI, higher tumor grade, more frequent lymphovascular space invasion, and elevated PD-L1 expression. Moreover, the 2023 FIGO staging system demonstrated superior performance in capturing the locally aggressive features of MMRd tumors relative to the 2009 edition. Within the MMRd cohort, the overall difference in combined positive score reached nominal significance (p = 0.049) but did not survive FDR correction (q = 0.290). Nevertheless, at the 1% and 5% cutoffs, MutLα-deficient tumors consistently showed higher PD-L1 positivity than MutSα-deficient tumors, with both associations remaining significant after FDR adjustment (q = 0.046 for both). Further subgroup analysis within the MutLα loss pathway revealed that isolated MLH1 loss was associated with a lower rate of CPS ≥ 1% (85.7%) compared with isolated PMS2 loss (91.3%) and combined MLH1/PMS2 loss (89.3%), in contrast. No significant heterogeneity in PD-L1 expression was observed across the MutSα-deficient subgroups. Conclusions: MMRd endometrial cancer heterogeneity is primarily driven by MutSα and MutLα deficiency. MutSα loss associates with higher PD-L1 expression, suggesting a favorable immune profile warranting further study. Isolated MLH1 loss correlates with the lowest PD-L1 and aggressive features. These findings refine biological understanding and provide a hypothesis-generating rationale for biomarker-guided stratification in immunotherapy.