GJB2 Drives LUAD Progression via cAMP-Mediated M2 Macrophage Polarization through the PKA-CREB Pathway

M2 macrophage polarization drives lung adenocarcinoma (LUAD) progression, but the underlying regulatory mechanisms remain unclear, and the role of gap junction protein GJB2 in LUAD is undefined. This study investigated GJB2 expression patterns and its ability to regulate macrophage polarization via cAMP transfer. TCGA database analysis was used to correlate GJB2 expression with prognosis; GJB2 knockdown (KD) and overexpression (OE) models were established in A549 and NCI-H1975 cells; cell proliferation, migration, invasion, and apoptosis were assessed using EdU, Transwell, and flow cytometry assays; co-culture systems of LUAD cells with THP-1-derived macrophages were developed; cAMP agonists/inhibitors and PKA-CREB pathway analysis were applied to elucidate mechanisms; and in vivo validation was performed using BALB/c nude mouse xenograft models. Results showed that GJB2 was significantly upregulated in LUAD tissues and correlated with reduced overall survival. GJB2-KD inhibited proliferation, migration, and invasion while promoting apoptosis, whereas GJB2-OE produced opposite effects. GJB2 mediated gap junction-dependent cAMP transfer from LUAD cells to macrophages, activating the PKA-CREB axis to induce M2 polarization, and cAMP agonists reversed GJB2-KD effects. In vivo experiments demonstrated that GJB2-KD suppressed tumor growth, decreased serum cAMP and M2 cytokines, and inhibited PKA/CREB phosphorylation. Collectively, the GJB2-cAMP-PKA-CREB axis drives M2 polarization and LUAD progression, establishing GJB2 as a novel prognostic biomarker and therapeutic target. Abbreviations: LUAD, lung adenocarcinoma; KD, knockdown; OE, overexpression; EdU, 5-ethynyl-2'-deoxyuridine; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element-binding protein.