Background <p>Early administration of IL-6R blockade is effective in adult-onset Still’s disease (AOSD), but the underlying immune alterations during combined immunotherapy remain unclear.</p> Methods <p>We employed high-dimensional single-cell mass cytometry and an unbiased bioinformatics pipeline to characterize the immune landscape in treatment-naïve AOSD patients, stable AOSD patients after 24&#xa0;weeks of IL-6R blockade plus methotrexate and prednisone, and matched healthy controls. Cytokine profiling was conducted using a high-throughput cytometric bead array, and potential regulatory networks were identified using the <i>PerformanceAnalytics</i> package. Validation was performed via flow cytometry and mRNA sequencing.</p> Results <p>We identified 22 peripheral immune cell populations and characterized their composition and phenotypic markers. Treatment-naïve AOSD patients exhibited significant depletion of CD4⁺ T cells and B cells, along with excessive activation of CD8⁺ T cells and a previously unreported CD45⁺CD3⁻CD19⁻CD10⁻CD66a⁺ population, findings that were validated in an independent AOSD cohort. mRNA sequencing revealed the proinflammatory role of CD8⁺ T cells. Notably, these dysregulated immune profiles were markedly restored following immunotherapy. IL-18, IL-21, and IFN-γ demonstrated strong associations with adaptive immune cells and AOSD clinical indices.</p> Conclusions <p>Combined IL-6R blockade effectively modulates immune dysregulation in refractory AOSD, reversing key pathological immune alterations and highlighting its therapeutic potential.</p> Graphical Abstract <p></p>