The macrophage opera: from metabolic prolog to oncogenic crescendo in metabolic dysfunction-associated steatotic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory subtype, metabolic dysfunction-associated steatohepatitis (MASH), have emerged as a pressing global health crisis, imposing escalating clinical and economic burdens worldwide. The disease continuum progresses from isolated hepatic steatosis through inflammatory steatohepatitis and progressive fibrosis to cirrhosis, markedly elevating the risk of hepatocellular carcinoma (HCC). As key orchestrators of innate immunity and tissue homeostasis, hepatic macrophages dynamically mediate disease initiation, progression, and malignant transformation across this spectrum. This review systematically synthesizes current knowledge on macrophage-centric pathophysiological mechanisms spanning the MASLD-MASH-HCC axis and evaluates state-of-the-art macrophage-targeted therapeutic strategies. We first delineate the developmental origins, functional heterogeneity, polarization plasticity, and spatially resolved architecture of hepatic macrophage populations, emphasizing their transcriptional and phenotypic diversity that extends beyond the traditional M1/M2 paradigm. Stage-specific mechanisms are further elucidated, ranging from lipotoxic stress-induced inflammatory signaling and Kupffer cells(KCs)-dependent monocyte recruitment to crown-like structure formation and the role of disease-associated macrophage subsets. These macrophage-driven processes collectively promote an immunosuppressive niche and confer therapy resistance in established HCC. Finally, emerging therapeutic paradigms aimed at modulating macrophage recruitment, polarization, metabolism, and effector functions via nanomedicine and cell-based modalities are critically appraised. Unraveling the spatiotemporal dynamics of macrophage behavior during MASLD-HCC progression is pivotal for designing stage-specific interventions to halt disease advancement and improve long-term patient survival.