Multi-omics analysis reveals that CAPG positive macrophages are key immunosuppressive drivers and prognostic determinants in the ferroptosis landscape of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by substantial heterogeneity and immune tolerance, and its therapeutic efficacy is profoundly influenced by the immune microenvironment. Ferroptosis, an iron-dependent form of regulated cell death, is closely linked to tumor immune regulation. We conducted an integrative multi-omics analysis to systematically delineate the composition and function of the ferroptosis-immunity network in HCC. Using TCGA data, we identified ferroptosis-related prognostic genes. By integrating these with immune features via weighted gene co-expression network analysis (WGCNA), we defined 55 ferroptosis-immune microenvironment-related genes (FIMRGs). Single-cell transcriptomic analysis showed that, among immune cell types, macrophages exhibited the highest ferroptosis-immunity activity. Spatial transcriptomics revealed that macrophages with high ferroptosis signaling (FehighMac) preferentially infiltrated tumor nests. These macrophages engaged in robust interactions with T cells via ligand-receptor axes such as ICAM1-ITGAX/ITGB2, TNF-TNFR, and LGALS9-CD45, potentially promoting T-cell exhaustion and shaping an immunosuppressive microenvironment. We identified CAPG-positive macrophages (CAPG + Mac) as the key driver of this process. Characterized by suppressed ferroptosis, enhanced glutathione metabolism, and upregulated immune checkpoints, CAPG + Mac appear to foster an immune-tolerant microenvironment. A prognostic model constructed from CAPG + Mac signature genes effectively stratified HCC patients into high- and low-risk groups and demonstrated stable predictive performance in external validation. This study reveals that CAPG + Mac putatively modulate ferroptosis signaling to influence immune homeostasis, highlighting them as a key target for HCC progression and immunotherapy responsiveness.