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Immunotherapies have significantly improved the prognosis of patients with advanced hepatocellular carcinoma (HCC), although more than 70% of patients still do not respond to this first-line treatment. Many new combination strategies are currently being explored, which drastically increases the need for preclinical models that would allow large-scale testing of new immunotherapies and their combinations. We developed several in ovo (in the egg) human liver cancer models, based on human tumor xenografts of different liver cancer cell lines on the chicken embryo's chorioallantoic membrane. We characterized the angiogenesis, as well as the collagen accumulation and tumor immune microenvironment, and tested atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) treatment. Our results show the involvement of chicken immune cells in tumor growth, reproducing a classical non-inflamed "cold" as well as inflamed "hot" tumor status, depending on the in ovo liver cancer model. The treatment by atezolizumab and bevacizumab was highly efficient in the "hot" tumor model PLC/PRF/5 in ovo with the reduction of tumor size by 76% (p ≤ .0001) compared with the control, whereas the efficacy was limited in the "cold" Hep3B in ovo tumor. The contribution of the anti-PD-L1 blockade to the anti-tumoral effect in the PLC/PRF/5 in ovo model was demonstrated by the efficacy of atezolizumab monotherapy (p = .0080, compared with the control). To conclude, our study provides a detailed characterization and rational arguments that could help to partially replace conventional laboratory animals with a more ethical model, suited to the current needs of preclinical research of new immunotherapies for liver cancer., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.