Enhancer-mediated NR2F2 recruitment activates BGN to promote tumor growth and shape tumor microenvironment in papillary thyroid cancer.

Biglycan (BGN), a component of the extracellular matrix, has been closely associated with tumor progression. This study aimed to investigate the endocrine and paracrine roles of BGN in papillary thyroid carcinoma (PTC) to elucidate the underlying molecular mechanisms driving PTC development. Multi-omics integration was used to assess BGN expression and its clinical relevance in PTC. Functional assays, including cell viability, colony formation, and cell cycle analysis, were used to evaluate the biological functions of BGN. RNA-seq identified key signaling pathways involved in BGN-mediated PTC progression. Immune cell infiltration and macrophage polarization were analyzed using single-cell RNA-seq and flow cytometry. CRISPR interference was employed to suppress BGN enhancer activity, while luciferase assays confirmed NR2F2's role in regulating BGN expression. The therapeutic potential of the NR2F2-specific inhibitor CIA1 was tested in PTC cell lines and mouse models. BGN overexpression in malignant PTC cells evaluated by BayesPrism deconvolution was linked to poor clinicopathological features in PTC. BGN knockdown inhibited cell proliferation and induced cell cycle arrest, which was rescued by recombinant BGN. Tumor-derived BGN activated the AKT signaling pathway, promoting tumor growth. Additionally, high BGN expression facilitated M2 macrophage polarization and immune evasion through TLR4 signaling. The NR2F2-BGN axis activated BGN transcription and AKT signaling. CIA1 treatment reduced BGN expression, suppressed cell proliferation, and modulated macrophage polarization. Our findings highlight the NR2F2-BGN axis as a critical regulator of PTC progression. Targeting this axis offers a promising therapeutic strategy for PTC treatment and immune microenvironment modulation.