Liver cancer is the sixth most common cancer worldwide, the fourth leading cause of cancer-related deaths, and the second most common cause of death from cancer for men [1]. Hepatocellular carcinoma (HCC) is the main pathological type of primary liver cancer, accounting for 75–85% of primary liver cancers [2]. There are no obvious clinical symptoms of HCC in the early stage, and 70–80% of patients are diagnosed in the advanced stage. Because of the biological and anatomical characteristics of the liver, HCC can easily invade intrahepatic vessels, especially the portal vein system [3]. Portal vein tumor thrombus (PVTT) is the most common form of macrovascular invasion, which occurs in 44.0–62.2% of HCC patients [4]. Blocked portal vein blood flow by PVTT can increase portal vein pressure, leading to ascites, hepatic encephalopathy, liver failure, and gastrointestinal bleeding [5]. PVTT can also promote the spread of tumors throughout the liver parenchyma and affect the survival and prognosis of patients with HCC [2,6]. The median survival time of untreated PVTT patients is typically 2.7–4.0 months [7]. Sorafenib and lenvatinib have been recommended as first-line therapy for patients with HCC plus PVTT, but they have a poor response and survival benefits [2]. Patients treated with sorafenib alone had prolonged overall survival (OS) of only 2–3 months [4]. In addition to targeted therapy, alternative therapies such as transcatheter chemoembolization (TACE) and radiotherapy (RT) can improve the prognosis and prolong the survival time of HCC patients with PVTT [3]. In recent years, atezolizumab and bevacizumab have been recommended as first-line therapy for advanced HCC. With the development of immunotherapy, there are more treatment options for PVTT [8]. However, the exact mechanism of PVTT formation remains unclear, although several related signal transduction pathways or molecular pathways have been identified [9].

Most HCCs occur in the context of liver diseases, such as hepatitis B and C, all of which are accompanied by varying degrees of cirrhosis [10]. The regenerated hepatic lobule and fibrotic tissue compress the hepatic vein and form portal hypertension, which leads to different degrees of portal vein blood flow reflux. Elevated portal venous pressure and blood flow disturbance are the anatomical and hemodynamic bases of PVTT formation [9]. At the cellular and molecular levels, some studies have explored the relevant pathways for PVTT development such as FOXM1-miR-135a-MTSS1 and TGF-β-miR-34a-CCL22 [11,12]. Although abnormal values of gene expression and aberrant epigenetic modifications play key roles in PVTT formation, the molecular mechanisms underlying PVTT formation need to be extensively studied [13]. The occurrence and development of PVTT are closely related to the interaction and influence of various factors such as the body, tumor cells, and microenvironment. In this review, we summarize the research progress in mechanisms of PVTT formation from the aspects of tumor cell changes, tumor microenvironment (TME), and cell metabolism.