Immune landscape of hepatocellular carcinoma: From dysregulation of the immune responses to the potential immunotherapies

Abstract Hepatocellular carcinoma (HCC) presents a considerable global health burden due to its late diagnosis and high morbidity. The liver's specific anatomical and physiological features expose it to various antigens, requiring precise immune regulation. To the best of our knowledge, this is the first time that a comprehensive overview of the interactions between the immune system and gut microbiota in the development of HCC, as well as the relevant therapeutic approaches are discussed. Dysregulation of immune compartments within the liver microenvironment drives HCC pathogenesis, characterized by elevated regulatory cells such as regulatory T cells (Tregs), myeloid‐derived suppressor cells, and M2 macrophages as well as suppressive molecules, alongside reduced number of effector cells like T cells, natural killer cells, and M1 macrophages. Dysbiosis of gut microbiota also contributes to HCC by disrupting intestinal barrier integrity and triggering overactivated immune responses. Immunotherapy approaches, particularly immune checkpoint inhibitors, have exhibited promise in HCC management, yet adoptive cell therapy and cancer vaccination research are in the early steps with relatively less favorable outcomes. Further understanding of immune dysregulation, gut microbiota involvement, and therapeutic combination strategies are essential for advancing precision immunotherapy in HCC.