CXCL2/CXCR2 pathway regulates CD169high large macrophages to promote progression of malignant pleural effusion from lung adenocarcinoma

Background Malignant pleural effusion (MPE) correlates with poor prognosis. Tumor-associated macrophages dominate the immune microenvironment and govern MPE progression, while the functional heterogeneity of macrophage subsets in MPE remains poorly understood. CD169 + macrophages exhibit context-dependent tumor-regulatory functions in various malignancies, yet their phenotypic characteristics and biological roles in MPE remain uncharacterized. Methods CD169⁺ macrophages and their CD169 low small and CD169 high large subsets were characterized in PPE, IPE, and lung adenocarcinoma-associated MPE, as well as in a murine MPE model, by flow cytometry. Their associations with MPE control were analyzed. The effects of CXCL2/CXCR2 signaling on macrophage migration, proliferation, and apoptosis were evaluated using recombinant human CXCL2 and the CXCR2 inhibitor SB225002 in vitro , and the therapeutic effects of CXCR2 inhibition were assessed in vivo . Results CD169⁺ macrophages, including CD169 low small and CD169 high large macrophages, were significantly enriched in lung adenocarcinoma-associated MPE ( P < 0.05). Only CD169 high large macrophages were negatively associated with MPE control ( P < 0.05) and exhibited an immunosuppressive phenotype. Macrophages were the predominant CXCL2-expressing population in single-cell analysis. CXCL2 promoted macrophage migration, whereas CXCR2 inhibition with SB225002 attenuated this effect without affecting macrophage proliferation or apoptosis. In vivo , SB225002 reduced pleural effusion volume, CD169 high macrophage accumulation, and tumor burden. Conclusions We identified a distinct population of CD169 high large macrophages that is enriched in lung adenocarcinoma-associated MPE and exhibits an immunosuppressive phenotype. CXCL2/CXCR2 axis promotes macrophage migration and contributes to the accumulation of CD169 high macrophages in the MPE microenvironment, thereby facilitating MPE progression. These findings provide new insights into the myeloid-cell regulatory mechanisms underlying MPE and may represent a potential therapeutic strategy for lung cancer-associated MPE.