Hypomethylation of GNA15 Promotes Pancreatic Ductal Adenocarcinoma Progression and Macrophage M2 Polarization via STAT3‐CXCL8 Axis

The complexity of pancreatic ductal adenocarcinoma (PDAC) progression, coupled with the lack of effective immunotherapy, underscores the imperative to deepen our understanding of its mechanisms and identify suitable immune‐targeted interventions. The G protein alpha subunit 15 (GNA15) is significantly upregulated in PDAC and correlates with poor prognosis in patients with PDAC. Mechanistically, our study demonstrates that TET3 upregulates GNA15 expression through demethylation in PCs, and the highly expressed GNA15 activates the phosphorylation of STAT3 via the GP130‐JAK signaling pathway, thereby promoting the expression and release of CXCL8. Subsequently, CXCL8 released by PCs binds to CXCR1 or CXCR2 in macrophages to promote M2 polarization. Additionally, high GNA15 expression was associated with Gemcitabine resistance, and the combination of Reparixin and Gemcitabine has shown favorable antitumor efficacy in PDAC. Collectively, we elucidated that GNA15 drives PDAC progression and M2 macrophage polarization via the STAT3‐CXCL8 axis and established targeting GNA15‐STAT3‐CXCL8 as a novel strategy to improve PDAC therapies.