fig3

Figure 3. Metabolic reprogramming in HCC modulates a multi-cellular immune microenvironment. HCC metabolic reprogramming actively shapes an immune microenvironment by modulating the function of both immune and stromal cells. Key metabolic pathways, such as tryptophan, glutamine, and lactate metabolism, regulate immune cell functions. Tregs: Metabolites such as lactate, α-KG, and kynurenine promote Treg differentiation and function, supporting immune suppression in the TME. MDSCs: Tumor-derived factors such as GM-CSF and IL-6 drive MDSC expansion, which inhibits anti-tumor immunity. TAMs M2: Tumor cells and metabolic reprogramming influence TAM polarization, with factors such as VEGF-A and MMP-9 promoting tumor growth and metastasis. CD8⁺ T Cells: PLA2G2A⁺ CAFs and metabolic changes in HCC inhibit CD8⁺ T cell anti-tumor function via signaling pathways such as MAPK/Erk and NF-κB. DCs: Metabolic reprogramming affects the function of CD103⁺ DCs, essential for CD8⁺ T cell activation and immune surveillance. Metabolic changes in CAFs and Endothelial Cells promote tumor growth, angiogenesis, and immune evasion, contributing to a pro-TME. Additionally, metabolites such as lactate and exosomes from tumor cells further shape the immunosuppressive environment, promoting tumor progression and immune resistance. HCC: Hepatocellular carcinoma; α-KG: α-ketoglutarate; Treg: regulatory T cell; TME: tumor microenvironment; MDSCs: myeloid-derived suppressor cells; GM-CSF: granulocyte–macrophage colony-stimulating factor; IL-6: interleukin-6; TAMs: tumor-associated macrophages; VEGF-A: vascular endothelial growth factor A; MMP-9: matrix metalloproteinase-9; CD8⁺: cluster of differentiation 8 positive; PLA2G2A⁺: phospholipase A2 group IIA positive; CAFs: cancer-associated fibroblasts; MAPK: mitogen-activated protein kinase; Erk: extracellular signal-regulated kinase; NF-κB: nuclear factor kappa B; DCs: dendritic cells; HIF-1α: hypoxia-inducible factor 1α; AhR: aryl hydrocarbon receptor; EGF: epidermal growth factor; uPA: urokinase-type plasminogen activator.