Hepatocellular carcinoma (HCC) is a most deadly malignant disease worldwide, with no effective mechanism‐based therapy available. Therefore, following the “miracle” outcomes seen in a few patients at the advanced stages of melanoma or lung cancer, the immune checkpoint inhibitors (ICIs) immediately entered clinical trials for advanced HCC patients without pre‐clinical studies. Emerging data of clinical studies showed manageable toxicity and safety but limited therapeutic benefit to HCC patients, suggesting low response rate. Thus, one urgent issue is how to convert the liver tumors from cold to hot and responsive, which may rely on in‐depth mechanistic studies in animal models and large scale data analysis in human patients. One ongoing approach is to design combinatorial treatment of different ICIs with other reagents and modalities. Indeed, a phase 3 clinical trial showed that combination of atezolizumab and bevacizumab achieved better overall and progression‐free survival rates than sorafenib in unresectable HCC. This review highlights the value of animal models and the power of combining pre‐clinical and clinical studies in efforts to improve HCC immunotherapy.

SUMMARY The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells, and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH), and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation, and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

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The mechanisms underlying the recurrence and metastasis of hepatocellular carcinoma (HCC) are poorly understood. In 2015, Zhuang and her colleagues identified a unique histopathological structure in HCC tissues, which they dubbed VETC, standing for vessels that encapsulate tumor clusters. 1 In the VETC structure, sinusoid-like vessels form a cobweb-like network that encapsulates individual tumor cell clusters. These endotheliumwrapped tumor cell clusters were released into the blood stream and formed metastatic tumors in a manner independent of epithelial-mesenchymal transition (EMT), another wellknown tumor metastatic process. 2 Mechanistically, the authors found that angiopoietin-2 (Angpt2) secreted by tumor cells played a critical role in the induction of VETC formation and intrahepatic tumor metastasis and recurrence.In this issue, Zhuang's group report a very interesting functional relationship between androgen receptor (AR) and VETC formation in intrahepatic and extrahepatic metastasis of liver cancer. 3 AR is a member of the nuclear hormone receptor superfamily whose elevated expression has been implicated in HCC development. 4 Paradoxically, genetic deletion of AR in hepatocytes delayed mouse HCC initiation driven by diethylnitrosamine, but exacerbated later tumor growth and metastasis to the lung, demonstrating complex mechanisms of AR activity in HCC. 5 Consistently, an AR antagonist did not show significant therapeutic benefit for patients with HCC in clinical trials. 6 To further elucidate the roles of AR in HCC, the investigators examined nuclear AR contents in 241 HCC samples collected in the Cancer Center of Sun Yat-sen University. Interestingly, lower levels of nuclear AR and VETC formation significantly correlated with higher risk of HCC recurrence and poor survival. This data was validated in another cohort of patients with HCC using the TCGA dataset. Reduced AR expression was also associated with HCC cases with portal vein tumor thrombus. To explore a causative role of AR in VETC-dependent metastasis, the authors expressed mouse AR in Hepa1-6 hepatoma cells, which form VETC+ tumors. Overexpression of AR suppressed VETC formation in xenografts and also intrahepatic metastasis, while increasing the numbers and sizes of metastasized foci in the lung. Next, the authors interrogated the molecular mechanisms underlying the effects of AR.Their previous experiments showed that high expression of Angpt2 was required for VETC formation. 1 In the present study, the