Background <p>Sarcoidosis is pathologically characterized by non-necrotizing granulomas inflammation. Despite the high spontaneous remission rate, a remarkable number of sarcoidosis patients undergo persistent progression. Glucocorticoids are currently recommended as the first-line treatment for sarcoidosis, but the therapeutic responses showed a great heterogeneity in clinical practice. We investigated the role of macrophages and Th17.1 cells in the poor response to glucocorticoid and progression in the early-stage sarcoidosis.</p> Methods and main results <p>CyTOF was performed on the mediastinal lymph nodes and peripheral blood samples to probe the alterations of immune cells in sarcoidosis. Monocytes were enriched in sarcoidosis patients but with impaired functions of antigen processing and presentation. Meanwhile, Th17.1 cells were enriched and overactivated in sarcoidosis. Both macrophages and Th17.1 cells were recruited to the granuloma lesions by CCL2 and CXCL-9/10, respectively. The granulomas of sarcoidosis in lymph nodes were classified as 3 types: M1-like macrophage-dominated type (type I), M1/2-mixed macrophage type (type II) and M2-like macrophage-dominated type (type III). Type III granuloma with elevated Th17.1 cells and M2-like macrophages predict a poor therapeutic response of sarcoidosis patients. In addition, Th17.1 cells impaired the antigen phagocytic and processing ability of macrophages through CD47/SIRPα interaction. Blockade of CD47/SIRPα interaction significantly repressed the progression of sarcoidosis in mouse model.</p> Conclusions <p>Our study reveals a novel interaction between Th17.1 cells and M2-like macrophages in Type III granulomas potentially mediated through CD47-SIRPα, which may contribute to impaired antigen processing and glucocorticoid resistance in sarcoidosis. Therapies targeting this molecular pathway represent a promising direction for developing new sarcoidosis treatments.</p> Graphical Abstract <p></p>