Elevated IgG levels induce an M2‑to‑M1 phenotypic shift in mucosal macrophages and restrict the growth of invasive sphenoid sinus pituitary adenomas

Although invasive pituitary adenomas (PAs) commonly invade the sellar floor and violate the dura mater, complete penetration of the sphenoid sinus mucosa is uncommon, and thus, mapping of the tumor‑mucosa immune landscape is warranted. In the present study, clinical PA specimens were analyzed via H&E staining, Masson's trichrome staining and immunohistochemistry. Spatial immune architecture and activation states were mapped by multiplex immunofluorescence staining. Two models, air‑liquid interface culture of mucosal tissue explants and co‑culture of dissociated mucosal cells with primary PA cells, were used to test mucosa‑derived inhibition. Cytokines were quantified using ELISAs. Tumor growth inhibition and cell cycle changes were assessed by flow cytometry. Intracellular signaling was examined by western blotting. Macrophage phagocytosis of pHrodo™‑labeled tumor cells was quantified. The sphenoid sinus mucosa retained structural integrity. Both co‑culture systems reduced proliferation (lower Ki‑67 labeling) and increased cell death (higher annexin V/PI positivity) in primary PA cells, with effects more pronounced in co‑cultures with enzymatically digested mucosa than with intact mucosal tissue fragments. Macrophages were predominant at the invasive fronts and repolarized from immunoregulatory (M2) to pro‑inflammatory (M1) phenotypes. Mucosal macrophages expressed significantly more IFN‑γ than their intratumoral counterparts. High IFN‑γ levels were associated with lower Ki‑67 levels, and exogenous IFN‑γ suppressed PA cell proliferation and migration via S‑phase arrest and Janus kinase‑STAT1 activation. Mucosal B cell‑derived IgG levels were higher than IgA levels and were associated with M1‑like macrophages rather than M2‑like macrophages. IgG treatment increased M2 macrophage pro‑inflammatory cytokine levels, particularly IL‑6 levels. IL‑6 induced G1‑phase arrest. Combined IL‑6 and IFN‑γ treatment increased STAT1 phosphorylation compared with that observed after IFN‑γ treatment alone, without increasing STAT3 activation beyond the activation induced by IL‑6 alone, thereby reducing PA cell proliferation and migration. In co‑culture experiments, anti‑CD47 monoclonal antibody enhanced macrophage‑mediated antibody‑dependent cellular phagocytosis and was associated with reduced tumor cell proliferation. In conclusion, the sphenoid sinus mucosa establishes an immune barrier centered on M1‑polarized macrophages and IgG‑high B cells. This network generates an IFN‑γ/IL‑6 gradient that restricts local PA progression, and highlights macrophage/B cell‑directed and CD47‑targeted approaches as potential adjuncts to surgery.