ANGPT2 Drives Thyroid Cancer Progression Through PI3K/AKT Signaling and Correlates With Poor Prognosis and Immune Infiltration

ABSTRACT Objectives Angiopoietin‐2 (ANGPT2) is known to participate in tumor progression and immune modulation across multiple malignancies. Nevertheless, its expression pattern, prognostic value, and biological function in thyroid cancer (THCA) have not been comprehensively investigated. Methods An integrative analysis using multiple public databases was conducted to evaluate the expression pattern, prognostic value, and potential functional pathways associated with ANGPT2 in THCA. Experimental validation was performed using human THCA tissues and TPC‐1 cell lines. Quantitative PCR, Western blotting, and multiplex immunofluorescence were used to assess ANGPT2 expression and its correlation with immune infiltration. Stable ANGPT2‐overexpressing TPC‐1 cells were constructed, and functional assays, including CCK‐8, wound healing assay, and Western blotting, were employed to evaluate proliferation and migration. Results ANGPT2 was significantly upregulated in THCA tissues compared with normal thyroid tissues (median transcript per million: 3.29 vs 3.13, p < 0.001) and associated with poor overall survival (HR = 5.37, 95% CI: 1.22–23.63, p = 0.013) and relapse‐free survival (HR = 2.76, 95% CI: 1.11‐6.87, p = 0.023). Bioinformatics analysis suggested involvement in immune regulation and PI3K/AKT signaling. Experimental validation confirmed a positive correlation between ANGPT2 expression and CD4 + T cells infiltration ( r = 0.69, p = 0.03). Functional studies revealed that ANGPT2 overexpression significantly enhanced THCA cell proliferation and migration, accompanied by upregulation of MMP2 and MMP9. These effects were partially reversed by the PI3K phosphorylation inhibitor Pilaralisib, indicating that ANGPT2 may promote tumor progression through PI3K/AKT‐dependent mechanisms. Conclusions ANGPT2 promoted thyroid cancer cell proliferation and migration through activation of the PI3K/AKT signaling pathway, and was closely linked to altered immune cell infiltration. Its overexpression was associated with unfavorable prognosis, underscoring its potential as both a prognostic biomarker and a therapeutic target in thyroid cancer.