Immune System and Hepatic Stellate Cells’ Crosstalk in Liver Fibrosis: Pathways and Therapeutic Potential

Liver fibrosis, characterized by the excessive deposition of extracellular matrix (ECM) driven by hepatic stellate cells (HSCs) activation, remains a critical challenge due to its progression to cirrhosis and hepatocellular carcinoma (HCC). This review clarifies the complex crosstalk between the immune system and HSCs, highlighting key cellular players including macrophages, natural killer (NK) cells, regulatory T cells (Tregs), and their cytokine-mediated signaling pathways that regulate fibrogenesis and fibrosis resolution. We describe pivotal molecular mechanisms such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), Wnt/β-catenin, and NF-κB signaling in HSCs modulation, emphasizing their interplay with immune responses. Novel therapeutic strategies targeting this complex immune-HSCs interaction, ranging from immunomodulatory agents, macrophage polarization, and NK cell-based therapies, to stem cell-derived exosomes, offer promising opportunities for preventing and reversing fibrosis. We further discuss innovative combination therapies integrating immunotherapies with antifibrotic agents, personalized strategies based on immune profiling, and the challenges of immune heterogeneity in fibrosis management. This review discusses recent advances in molecular interplay of immune system and HSCs, highlighting novel therapeutic targets, and future perspectives for managing chronic liver diseases.