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

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.