AUTHOR=Jiang Peng , Yu Jiaxin , Zheng Yunfeng , Tian Chenfan , Tu Yuan , Gong Chunxia , Yu Hangkun , Luo Yi , Hu Zhuoying 

TITLE=Prognostic significance and immune infiltration analysis of HMGA2 in endometrial cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1559278

DOI=10.3389/fimmu.2025.1559278

ISSN=1664-3224

ABSTRACT=BackgroundHMGA2, as a transcription factor, facilitates oncogenesis and malignant progression by coordinating cell cycle dysregulation, compromising DNA repair machinery, and suppressing cancer cell apoptosis. However, its roles in prognostication and tumor immune microenvironment modulation in endometrial cancer (EC) remain incompletely defined.MethodsWe systematically analyzed HMGA2 expression patterns and clinical prognostic value in EC using bioinformatics strategies, including TCGA and GTEX data mining, as well as single gene expression analysis. Functional enrichment analysis (GSEA and KEGG) identified HMGA2-associated pathways. The correlation between HMGA2 and immune infiltration was assessed via TIMER and TISIDB. Subsequent in vitro (proliferation, migration, colony formation) and in vivo (xenograft models) experimental were used to validate HMGA2’s role in promoting EC progression. The correlation between HMGA2 and macrophage markers (CD86 and CD206) was validated through clinical tissue samples by IHC. Finally, a recurrence-predictive nomogram incorporating HMGA2 with clinicopathological parameters was established.ResultsHMGA2 exhibited significant upregulation in endometrial cancer (EC) tissues and correlated with poor patient prognosis. Immunoassay showed that high expression of HMGA2 was negatively correlated with infiltration of various immune cells, especially M1 macrophages. Cytological experiments showed that knocking down HMGA2 significantly inhibited EC cell proliferation, migration, invasion, and drug resistance, while overexpression of HMGA2 promoted the above phenotype; Animal experiments showed that knocking down HMGA2 significantly inhibited the growth of EC tumors and the expression of M1 macrophage marker CD86. The combination of HMGA2 inhibitors and targeted macrophage immunotherapy (CD47 monoclonal antibody) had the better tumor suppression effect. Clinical sample analysis found that high expression of HMGA2 was significantly negatively correlated with CD86 and positively correlated with CD206 expression. Patients with low HMGA2 expression showed enhanced immune therapy responsiveness. The nomogram model based on HMGA2 and clinical pathological parameters showed better predictive performance (AUC=0.855, sensitivity=79.0%, specificity=76.8%).ConclusionHMGA2 is a potential diagnostic and prognostic biomarker for the EC. HMGA2 may drive the occurrence and development of EC by inhibiting the infiltration of immune cells, especially M1 macrophages. Therapeutic targeting of HMGA2 is a novel strategy for EC intervention.