Introduction Endometrial carcinoma is a common gynecologic malignancy, and lymph node metastasis greatly affects patient outcomes. Proteogenomics analysis has emerged as a powerful tool for identifying molecular mechanisms involved in cancer progression and metastasis, offering potential for biomarkers discovery and personalized treatment strategies.

Methods In this study, we utilized WES, proteomics, and multiplex immunohistochemistry to investigate the metastasis patterns of different molecular subtypes in a cohort of 96 EC patients with lymph-node metastasis and 126 without metastasis. Our aim was to elucidate the molecular characteristics that distinguish between these two groups and identify potential biomarkers for metastasis.

Results Proteogenomics analysis identified two distinct metastasis patterns of EC associated with TME. One pattern is characterized by an immune-cold phenotype, which is predominantly observed in patients with the MSI subtype. These patients often exhibit JAK1 mutations, defects in immunoproteasome components and HLA complexes, leading to deficiencies in antigen presentation pathways, resulting in immune evasion. The other is characterized by an immune-hot phenotype, mainly distributed in the CNL and few MSI subtype, with significant infiltration of macrophages and upregulation of integrin pathways, promoting tumor cells to undergo mesenchymal transition. Additionally, we explored and validated three consensus biomarkers shared across diffrerent molecular subtypes for predicting lymph-node metastasis.

Conclusion/Implications Our research provides an unprecedented large-scale multi-omics resource of lymphatic metastasis EC, offering novel insights and new biomarkers for effectively stratifying high-risk patients for lymphatic metastasis. We have deciphered two distinct metastasis patterns in EC, which can be exploited for the development of personalized screening and targeting strategies.