Uncovering immune dysfunction in ACLF: Cellular mechanisms, molecular pathways, and therapeutic frontiers.

Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterised by acute hepatic decompensation, multi-organ failure, and high short-term mortality in patients with cirrhosis. A hallmark of ACLF is profound immune dysfunction, which contributes to excessive organ-specific inflammation and impaired host defence, predisposing patients to infection, multi-organ failure and death. This review aims to elucidate the cellular and molecular mechanisms implying systemic immune dysfunction in ACLF, highlighting key pathophysiological pathways and their clinical significance. We provide an overview of ACLF, including its global clinical impact, in the context of immune dysfunction as a central driver of disease pathogenesis. The discussion focuses on alterations in innate immunity, including impaired neutrophil and monocyte phagocytosis, excessive neutrophil extracellular trap (NET) formation, and monocyte/macrophage dysfunction, which contribute to immuneparesis and exaggerated inflammation in an organ-specific manner. Also, dysregulation of natural killer (NK) cell cytotoxicity and adaptive immune dysfunction, including changes in T-cell subpopulations and B-cell antibody production in ACLF, are adressed. We further dissect the emerging evidence of molecular pathways driving dysfunction of immune cells and their impaired ability to control infections in ACLF, emphasising the roles of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs), toll-like receptor (TLR) signalling, oxidative stress, mitochondrial dysfunction, epigenetic/metabolic reprogramming and immune checkpoint molecules. In addition, the review explores immune cell communication within the innate and adaptive immune systems, as well as interactions with parenchymal and non-parenchymal cells across organs affected by ACLF. Particular attention is given to inter-organ crosstalk involving the liver, circulation, brain, gut, and kidney. Finally, we summarise recent preclinical and clinical advances in biomarkers of immune dysfunction and immunomodulatory therapeutic strategies aimed at restoring immune homeostasis in patients with ACLF.