Hepatocarcinogenesis is a stepwise process. Chronic hepatitis virus infection and fat-induced steatosis (NASH), the major etiological factors of HCC, drive liver inflammation and tissue damage. Excessive alcohol consumption also induces liver damage. Damage in the liver disrupts the hepatic vasculature and perturbs proper blood flow and O₂ supply, creating a hypoxic microenvironment. Hypoxic Kupffer cells, newly recruited macrophages, and hepatocytes activate hepatic stellate cells (HSCs) in the liver, which robustly deposit collagen, leading to fibrosis and then cirrhosis, which further intensifies hypoxia. When HCC is developed, hypoxia is even more severe. The growth of HCC outpaces the growth of blood vessels. Moreover, HCC cells consume all available O₂. Different current HCC treatments, such as TAE/TACE and TKIs, further induce hypoxia. Hypoxia affects the activities of different innate immune cells, such as NK cells. Hypoxia also induces the infiltration and accumulation of many different types of immunosuppressive innate immune cells, including TAMs, MDSCs, and neutrophils, in the microenvironment of HCC. The O₂ level decreases along with HCC development, driving the formation of an immunosuppressive microenvironment.