Immune cells in liver injury: from pathogenic mechanisms to immunotherapy

Immune regulation is an essential process via which the immune system detects initial damage signals and initiates a response to preserve microenvironmental balance. In chronic liver illnesses (such as NAFLD, NASH, or viral hepatitis), a disruption in homeostasis results in sustained inflammation and the progression of liver fibrosis, a critical factor influencing long-term morbidity and death in patients. Liver inflammation is a multifaceted physiological reaction triggered by the combined influence of several signals from both internal and external sources. Recent advancements in single-cell and spatial transcriptomics have elucidated the mechanisms that regulate the heterogeneity, spatial distribution, and autophagic characteristics of diverse intrahepatic immune cell populations, such as macrophages, neutrophils, T cells, and non-classical lymphocytes. The immune responses meticulously govern the activation of hepatic stellate cells (HSCs), their subpopulation dynamics, and their transdifferentiation into myofibroblasts via a network of chemokines and cytokines. Due to the considerable unmet clinical requirements in NAFLD/NASH, thorough investigation of the mechanisms underlying liver inflammation and fibrosis has resulted in the identification of numerous promising treatment targets. This review intends to systematically elucidate the interactions between inflammatory mediators and immune cells, alongside the fibrotic signaling pathways and their regulation mechanisms in sick livers. It emphasizes recent clinical advancements in cell therapy for liver injury treatment, aiming to establish a theoretical basis for precise therapies in liver fibrosis.