Single-cell analysis of 45 blood samples from hepatitis B patients with acute-on-chronic liver failure (ACLF) identified distinct immune cell populations that orchestrate disease progression. VCAN+CD14+ monocytes with activated interferon genes drive early inflammatory storms, while hyperinflammatory CXCR2+ neutrophils and CD163+ monocytes correlate with disease deterioration. Cytotoxic T-cells become functionally impaired and depleted in progressive cases. This research provides the most detailed immune landscape of ACLF progression to date, revealing how specific monocyte and neutrophil populations create a cascade from initial viral reactivation to organ failure. The identification of CXCR2+ neutrophils as both inflammatory drivers and T-cell suppressors suggests these cells orchestrate the transition from protective immunity to pathological inflammation. For hepatitis B patients, this work illuminates why some develop life-threatening liver failure while others recover, potentially enabling earlier intervention. The study's limitation is its focus on circulating rather than liver-resident immune cells, though the findings align with known ACLF pathophysiology. These immune signatures could serve as prognostic biomarkers and therapeutic targets, particularly CXCR2 inhibition, which showed promise in reducing inflammation.