Macrophage Polarization in Sarcoidosis: Implications for Granuloma Formation, Fibrosis, and Therapeutic Strategies

Sarcoidosis is a multisystem granulomatous disease with a complex and incompletely understood immunopathogenesis. Macrophages and T lymphocytes play pivotal roles in granuloma formation and disease progression through dynamic interactions involving cytokine signaling and immune regulation. Recent evidence suggests that macrophage polarization, particularly the balance between classically activated M1 macrophages and alternatively activated M2 macrophages, plays a critical role in inflammatory granuloma formation and fibrotic progression in pulmonary sarcoidosis. TH1-related cytokines, including interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), promote proinflammatory M1 polarization, whereas TH2-related cytokines, such as interleukin (IL)-4 and IL-13, drive M2 polarization, tissue remodeling, and fibrosis. Emerging transcriptional, single-cell spatial transcriptomic, and 3D organoid studies further demonstrate the remarkable heterogeneity of macrophages in sarcoid granulomas. Current and emerging therapeutic approaches, including corticosteroids, methotrexate, anti-TNF agents, leflunomide, Janus kinase inhibitors, and novel macrophage-targeted strategies (such as efzofitimod), may exert their effects, in part, by modulating these distinct macrophage activation pathways. This review summarizes the available evidence on macrophage polarization in sarcoidosis and provides an immunology-informed clinical framework for disease endotyping, biomarker-guided monitoring, and targeted therapeutic strategies to prevent fibrotic progression.