Purpose <p>The key genes and the remodeling of immune cell composition in Graves’ ophthalmopathy (GO) orbital adipose tissue remain unclear. We aimed to explore key genes and understand their association with immune components in GO pathogenesis.</p> Methods <p> The study analyzed the mRNA, lncRNA, and single-cell RNA sequencing (scRNA-seq) expression profiles of orbital adipose tissue from GO patients using GSE58331, GSE143789, and GSE194323 respectively to screen the differential expressed genes (DEGs), which were further subjected to pathway and network analyses, along with investigation of their association with immunocyte proportions.</p> Results <p>A total of 70 DEGs of GO orbital adipose were screened out and were closely associated with immune-related pathways. The intersection between WGCNA and PPI defined 17 hub genes. GO group presented significantly higher abundances of CD8⁺ T cells, CD8 naïve, and effector memory cells than the normal group. In processing scRNA-seq data, we found that the proportion of B cells, CD4⁺ T cells, CD8⁺ T cells, monocytes, and NK cells was significantly higher in the GO group than in the control. Among them, CSF1R, MRC1, VSIG4, and C1QA were downregulated considerably in monocytes in the GO group compared to the normal group, which were confirmed by RT-qPCR and immunofluorescence of monocytes from GO patients. Overexpression of C1QA markedly decreased the expression of the M1 macrophage marker CD86, while enhanced the M2 marker CD206. Most DElncRNAs at bulk and single-cell levels shared 9 interacting proteins encoded by the hub genes. RT-qPCR verified that lncRNA PCED1B-AS1 expression was up-regulated in monocytes from GO patients compared to control.</p> Conclusion <p>GO involves gene expression alterations and immune cell remodeling in orbital adipose tissue. The downregulation of C1QA in monocytes and its role in promoting M2 macrophage polarization suggest its involvement in shaping the GO immune microenvironment.</p>