Integrated Immunophenotypic and ProMisE Molecular Profiling as Predictors of Immune Checkpoint Inhibitor Response in Endometrial Cancer

Background: Immune checkpoint inhibitors (ICIs) are an important treatment option for recurrent endometrial cancer (EC); however, responses vary widely. Although the ProMisE molecular classification provides prognostic and predictive insights, it does not fully explain the heterogeneity of ICI outcomes. Further characterization of the tumor immune microenvironment (TIME) is required to refine biomarker development. Methods: We retrospectively analyzed 72 patients with recurrent EC treated with ICIs. Immune markers, including CD8, CD68, CD163, CD47, CD276, PD-L1, and HLA class I, were quantified using digital pathology. Associations between immune markers, ICI response, and progression-free survival (PFS) were evaluated overall and within ProMisE molecular subtypes. Results: Responders exhibited a more immunologically active TIME, characterized by increased CD8⁺ T-cell infiltration in the central tumor (CT), whereas non-responders showed enriched CD68⁺ tumor-associated macrophages (TAMs) at the invasive margin (IM) and higher CD47 expression. Distinct immune landscapes were observed across ProMisE subtypes. Mismatch repair-deficient (MMRd) tumors showed high CD8 ⁺ T cell infiltration, no specific molecular profile (NSMP) tumors exhibited intermediate immune activation but variable CD47 expression, and p53-abnormal (p53abn) tumors demonstrated the most immunosuppressive profile with high CD47 expression and TAM density. Subtype-specific analyses revealed that PFS was predicted by different immune determinants, including CD8 ⁺ T cell infiltration in MMRd, CD47 expression level in NSMP, and CD68IM in p53abn. Conclusions: Tumor immune phenotypes provide predictive information beyond molecular classification alone. Integrating ProMisE classification with immunological profiling enables more precise stratification of ICI benefits. Distinct TIME features across subtypes underscore the need for subtype-tailored immunotherapeutic strategies.