In hepatocellular carcinoma (HCC), chronic inflammation and vascular abnormalities often promote an environment characterized by hypoxia, immunosuppressive cell infiltration (M2-activated macrophages, T regulatory cells and myeloid-derived suppressor cells) and upregulation of immune checkpoints. These immunosuppressive cues lead to impaired effector CD8+ T lymphocyte infiltration and function, and ultimately to immune evasion. Reactivation of the immune response is critical to overcoming treatment resistance in HCC. Large clinical trials of anti-PD-1 blockade therapy are ongoing, and interim analyses showed promising responses in a subset of patients. The current challenge is to rationally combine anti-PD-1 antibodies with the existing drugs to substantially increase survival more broadly in HCC patients. Antiangiogenic multikinase inhibitors (sorafenib, regorafenib, lenvatinib) have shown efficacy in HCC. These drugs work in part by VEGF pathway inhibition in tumor endothelial cells, which can delay tumor growth. If the antivascular effects are too pronounced, treatment leads to increased hypoxia, inflammation, and fibrosis in the tumor tissues. These effects may affect anti-tumor immune response, which are critical for achieving durable treatment responses. Thus, successful implementation of combination therapies will require synergy between these interventions to reduce angiogenesis, modify vascular function, reverse the immunosuppressive environment and activate anti-tumor immunity in HCC.
