Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics

Liver macrophages are master regulators of disease progression and resolution, whose functions transcend the simplistic M1/M2 dichotomy. This review synthesizes cutting-edge evidence to establish a dynamic, subset-centric paradigm for understanding macrophage plasticity. In acute liver injury, we delineate how temporally segregated subsets (e.g., early CCR2 + vs. late MerTK + macrophages) sequentially orchestrate damage and repair. In chronic settings—including HBV infection, MASLD/MASH, and fibrosis/cirrhosis—we reveal a complex coexistence of functionally opposed subsets that concurrently drive pathology (e.g., CD9 + TREM2 + macrophages) and promote resolution (e.g., CD300E + macrophages). This refined understanding underpins a critical appraisal of the evolving therapeutic landscape, which is pivoting from broad immunosuppression towards precision strategies. These include pharmacological targeting of specific recruitment or signaling pathways, adoptive transfer of reparative subsets, and innovative engineered cell therapies (e.g., signal-converting CAR-Ms). By framing macrophage functional duality within the “friend or foe” paradigm, this review provides a conceptual framework for developing subset-specific therapies that harness the beneficial while mitigating the harmful faces of hepatic macrophages. We highlight that the key translational challenge lies in mastering macrophage heterogeneity—requiring resolution of in vivo dynamics, cross-species discrepancies, and achievement of durable, context-specific modulation. The future of “macrophage medicine” hinges on integrating spatial multi-omics and advanced imaging to enable spatiotemporally precise interventions, ultimately leveraging the cell’s inherent plasticity for therapeutic gain.