TIPARP promotes M2-like macrophage polarization and associates with T2D myeloid alterations and PDAC progression

Type 2 diabetes (T2D) is associated with increased pancreatic ductal adenocarcinoma (PDAC) risk, and diabetes-associated myeloid alterations may contribute to this relationship. We integrated single-cell analyses, Mendelian randomization (MR), and cellular and mouse models to investigate TIPARP-associated myeloid states. TIPARP expression was enriched in T2D classical monocytes, with predicted interactions involving macrophage-like monocytes. MR suggested a nominal association between genetically predicted higher TIPARP expression and PDAC risk (odds ratio [OR] = 2.15, p = 0.0044), with colocalization evidence (posterior probability of hypothesis 4 [PPH4] = 0.8023). TIPARP overexpression promoted M2-like polarization in THP-1-derived and primary human macrophages with PI3K-AKT involvement. Conditioned media from TIPARP-overexpressing macrophages enhanced PDAC cell proliferation and migration, while macrophage co-injection was associated with larger xenograft tumors. Matched blood and tumor samples showed associations between circulating TIPARP -positive ( TIPARP +) classical monocytes, intratumoral TIPARP + macrophages, and M2-like signatures. These findings suggest that TIPARP-associated myeloid alterations may represent a potential immunological link between T2D and PDAC progression.