Fig. 2: Mechanisms of resistance to immune checkpoint inhibitors in hepatocellular carcinoma.

Illustration of the various mechanisms through which HCC cells may develop resistance to immune checkpoint inhibitors (ICIs). 1) Mutation or altered expression of antigen-presenting molecules on tumor cells leading to reduced T-cell recognition. 2) Impaired antigen presentation. 3) Alterations in the tumor microenvironment, or secretion of immunosuppressive cytokines by tumor cells. 4) Impaired T-cell phenotype, or a physical barrier repressing T-cell infiltration. 5) Altered tumor recognition by T cells. 6) Recruitment of immunosuppressive macrophages, myeloid-derived suppressor cells (MDSCs), or regulatory T cells (Tregs) to the tumor microenvironment, suppressing the activation and proliferation of T cells. 7) Upregulation of alternate immune checkpoints in tumor cells, rendering standard ICIs ineffective. 8) T-cell exhaustion is characterized by the overexpression of multiple inhibitory receptors, diminishing the immune response. The figure underscores the complexity of the tumor-immune microenvironment and the multifaceted nature of immune resistance in HCC, highlighting the need for multi-targeted approaches.