Functional heterogeneity of macrophages in distinct niches of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, characterized by a highly complex and dynamic tumor microenvironment in which tumor-associated macrophages (TAMs) are particularly abundant. TAMs regulate tumor initiation, progression, metastasis, and therapy response, making them attractive targets. However, targeting TAMs remains challenging due to their remarkable plasticity and functional heterogeneity. Recent high-throughput multi-omics studies have revealed that the HCC microenvironment consists of distinct regions defined by cellular architecture, such as the fibrotic invasive margin, perivascular niche, poorly vascularized hypoxic/necrotic areas, and cancer stem cell niche, each associated with unique protumorigenic properties. This review summarizes TAM heterogeneity across liver niches, disease stages, and treatment contexts, and evaluates TAM-targeted strategies, emphasizing key unresolved challenges to improving HCC outcomes.