Tumor-Associated Macrophages in Hepatocellular Carcinoma: From Ontogeny and Heterogeneity to Immune Evasion and Therapeutic Targeting

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer morbidity and mortality worldwide and typically arises within a profoundly immunosuppressive tumor microenvironment (TME). Among the myeloid populations that infiltrate the HCC microenvironment, tumor-associated macrophages (TAMs) are numerically dominant and function as central orchestrators of tumor initiation, progression, and immune evasion. TAMs originate from both tissue-resident Kupffer cells and bone marrow–derived monocytes, and are shaped by TME-derived cues such as hypoxia, metabolic stress, and inflammatory mediators that polarize them toward a tumor-promoting, M2-like phenotype. Once activated, TAMs release pro-angiogenic and trophic factors that sustain vascular remodeling and tumor proliferation, and they induce epithelial–mesenchymal transition (EMT) and stemness-associated programs that facilitate invasion and metastasis. Concomitantly, TAMs suppress antitumor immunity through the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, the expression of PD-L1, and the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Clinically, a high density of TAM infiltration is strongly associated with aggressive disease features, early recurrence, and poor prognosis. Given their dual roles in promoting immune escape and therapeutic resistance, TAMs have emerged as critical nodes within the HCC ecosystem and as promising targets for translational intervention. This review summarizes current understanding of TAM ontogeny, phenotypic diversity, and functional heterogeneity in HCC, delineates the molecular and immunological mechanisms through which they drive tumor progression, and discusses emerging TAM-targeted therapeutic strategies with clinical potential including CSF1R inhibition, CD47–SIRPα blockade, and chimeric antigen receptor–macrophage (CAR-M) therapies.