Fig. 2

Cuproplasia in TME of HCC. The TME in HCC is marked by aberrant angiogenesis, immunosuppression, dysregulated ECM remodeling, hypoxia, reprogramming, and chronic inflammation, initiating tumorigenesis, growth, self-renewal, metastasis, and immune escape. Cuproplasia induces high expression of LOX2 or LOX4 in HCC cells, CAFs, and TAMs, leading to the release of factors such as VEGF, PDGF, HGF, and FGF. These factors promote endothelial cell survival, proliferation, and angiogenesis, while also upregulating MMP2 expression by CAFs, thereby enhancing HCC invasiveness. Furthermore, cuproplasia upregulates PDL1 expression in HCC cells, CAFs, TAMs, and NK cells, resulting in apoptosis and exhaustion of CD8 + T cells. Alongside other cytokines, chemokines, metabolic substances, ROS, exosomes, etc., an immunosuppressive TME ultimately develops. CAFs cancer-associated fibroblasts, ECM extracellular matrix, FAK focal adhesion kinase, FGF fibroblast growth factor, HCC hepatocellular carcinoma, HGF hepatocyte growth factor, LOX2 lysyl oxidase-like2, LOX4 lysyl oxidase-like4, MAPK Mitogen-Activated Protein Kinase, MMP2 Matrix metalloproteinase 2, NK cells natural killer cells, PI3K phosphatidylinositol 3-kinase, PDGF platelet-derived growth factor, PDL1 programmed death-ligand 1, RAS rat sarcoma, ROS reactive oxygen species, TAMs Tumor-associated macrophages, TAN tumor-associated neutrophils, TME tumor microenvironment, VEGF vascular endothelial growth factor