TGFBI deficiency facilitates tumor associated macrophages M2 polarization and angiogenesis to promote pancreatic neuroendocrine neoplasms progression

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) that influence tumor progression through immunomodulation, angiogenesis, and extracellular matrix remodeling. Transforming growth factor-beta-induced protein (TGFBI) has demonstrated context-dependent roles in cancer; however, its function in pancreatic neuroendocrine neoplasms (pNENs) remains unclear. This study investigates the role of TGFBI in the progression of pNENs and its interaction with TAMs. We employed lentiviral-mediated knockdown and overexpression systems to modulate TGFBI levels in pNEN cell lines (QGP-1, BON-1) and macrophage-like THP-1 cells. Functional assays, including CCK-8, EdU, transwell migration, and tube formation assays, were conducted to evaluate tumor proliferation, invasion, and angiogenesis. Tumor xenograft models were established to assess in vivo effects. Transcriptomic analyses, including RNA sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, were performed to explore the underlying molecular mechanisms. TGFBI is silenced in pNENs and associated with TAM M2 macrophage. Down-regulation of TGFBI in pNEN cells promoted proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Silencing TGFBI enhanced M2 macrophage polarization, as evidenced by increased CD206 expression and activation of the JAK2/STAT3 pathway. Additionally, TGFBI deficiency facilitated angiogenesis both in vitro and in vivo, accompanied by elevated VEGFA expression. Over-expression of TGFBI or treatment with recombinant protein reversed these pro-tumorigenic effects. TGFBI functions as a tumor suppressor in pNENs by modulating TAM polarization, angiogenesis, and tumor cell behavior, largely through the JAK2/STAT3 signaling pathway. These findings reveal a novel role for TGFBI in the TME of pNENs and suggest its potential as a biomarker and therapeutic target.