Beyond molecular classification: integrating signaling, subcellular, and immune reprogramming in endometrial cancer

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries, with rising incidence rates that have not been matched by equivalent improvements in survival outcomes, particularly for high-grade and advanced-stage disease. The landmark molecular profiling performed by The Cancer Genome Atlas consortium transformed EC classification by identifying four reproducible subtypes with distinct prognostic profiles: POLE-ultramutated, mismatch repair-deficient, copy-number low, and copy-number high. This reclassification has directly informed clinical guidelines, and, most recently, enabled three practice-changing regulatory approvals that established chemoimmunotherapy as a new first-line treatment paradigm for advanced disease, although regulatory indications differ according to MMR status. Yet molecular heterogeneity within EC involves much more than just genomic alterations to encompass coordinated changes in developmental signaling pathways, subcellular protein redistribution, epigenetic regulation, and tumor–immune crosstalk. This narrative review synthesizes current evidence across several interconnected dimensions of EC biology: aberrant WNT/β-catenin and mTOR signaling with compartment-specific expression patterns; cancer stem cell markers, including CD133, SOX2, and OCT4; γ-glutamyl transferase as a redox-linked biomarker; NOTCH pathway dysregulation, whose context-dependent, occasionally paradoxical relationship with prognosis complicates direct translation of NOTCH-targeted therapies from other tumor types; an expanded landscape of tissue and circulating microRNAs for grade discrimination and prognosis, extending well beyond our own previously reported miR-375/miR-190b panel; and the prognostic and therapeutic relevance of tumor-infiltrating lymphocytes, together with T-cell receptor repertoire profiling as an emerging complementary immune biomarker. We also discuss emerging frontiers, including circulating tumor DNA as a minimal residual disease tool, single-cell and spatial transcriptomics revealing tumor microenvironment architecture, and artificial intelligence-augmented digital pathology. Building on these axes, we propose an integrated conceptual model in which developmental signaling, subcellular protein trafficking, epigenetic and stemness reprogramming, and immune remodeling are mechanistically coupled, rather than independent processes. A multidimensional, integrative framework incorporating these axes is essential for bridging the current gap between biological complexity and clinical precision in EC.