Hepatocellular carcinoma metastasis-immune microenvironment crosstalk: emerging mechanisms and immunotherapy

Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer globally, imposes a heavy burden on global public health owing to its consistently high incidence and mortality rates. Owing to the characteristics of its tissue structure, HCC has a high propensity for metastasis. Unfortunately, most patients are diagnosed at the middle or advanced stage and present with metastasis. The occurrence of metastasis often indicates a severe deterioration of the condition and the loss of an opportunity for radical treatment. Thus, immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the first-line treatment for patients with advanced metastasis. The tumor immune microenvironment (TIME), as the core immune component within tumors, has been confirmed to be significantly associated with metastasis through the complex crosstalk with suppressive immune cells. This crosstalk dynamically participates in the metastatic cascade of HCC, assisting tumors in completing invasion and diffusion. The goal of immunotherapy is to restore the function of exhausted immune cells in the TIME. However, the complex immunosuppressive microenvironment often weakens treatment responses, posing severe challenges to the application of immunotherapies. Accordingly, there is an urgent need to deeply investigate the crosstalk among diverse cell types within the immunosuppressive microenvironment and to systematically elucidate the impact of such intercellular crosstalk on the HCC metastasis as well as the response to immunotherapy, so as to improve the clinical benefit rate of immunotherapy for patients with metastatic HCC. This review focuses on the dual role of immune cells in HCC metastasis and the novel mechanisms by which they promote the HCC metastatic cascade. It systematically summarizes current therapeutic strategies targeting the immunosuppressive microenvironment to combat HCC metastasis. On this basis, it prospectively proposes the future development direction of immunotherapy, providing more effective guidance for the clinical diagnosis and treatment of patients with metastatic HCC.