A New Approach to Improving Immunotherapy for Liver Cancer

Liver cancer, and in particular hepatocellular carcinoma, is one of the most aggressive cancers with the poorest prognosis worldwide. In most cases, it is diagnosed at advanced stages, when treatment options are very limited. Although immunotherapy has represented a significant advance in oncology, only a portion of patients with this type of cancer respond to these treatments.

Researchers from the Hepatology Group at Cima Universidad de Navarra have identified a new strategy that could improve the efficacy of immunotherapy in liver cancer. “G9a is a protein that acts as an epigenetic regulator, controlling which genes in tumor cells are activated or silenced. In this study, we found that elevated levels of G9a are associated with a weaker immune response to the tumor. In practice, this means that the cancer is able to ‘hide’ and avoid being attacked by the body’s defenses,” explain Drs. Maite G. Fernández-Barrena and Matías Ávila, principal investigators at Cima and co-directors of the study.

By inhibiting this protein using new experimental drugs, the researchers have managed to reverse the evasion effect. “The tumor becomes more visible to the immune system, key defense signals are activated, and the body’s ability to recognize and attack cancer cells increases,” explain the authors. The study has been published in the latest issue of Cell Reports Medicine.

Promising therapeutic combination

One of the study’s most significant findings is that combining these G9a inhibitors with immunotherapy (anti-PD-1 antibodies) significantly enhances the antitumor effect in animal models. “This combined activity reduces tumor growth and increases the infiltration of immune cells (T lymphocytes), thereby improving the response to immunotherapy, which is not very effective on its own. This approach is particularly important in a tumor such as liver cancer, where clinical experience indicates that the response to immunotherapy remains limited.”

This preclinical work, conducted at the Cancer Center of the University of Navarra Clinic, opens a new avenue for improving liver cancer treatment through the combination of epigenetic therapies and immunotherapy. “For tumors as difficult to treat as liver cancer, it is essential to continue exploring new therapeutic combinations that increase the efficacy of current treatments.”

The collaborative study was conducted within the framework of CIBEREHD (Biomedical Research Network Center for Liver and Digestive Diseases) and involved several leading national and international groups in the field of hepatology. It also received public funding from the Ministry of Science, Innovation, and Universities and the Government of Navarra, as well as support from private institutions such as the Spanish Association Against Cancer and the “la Caixa” Foundation.

“The collaboration and efforts of all the groups involved have been essential in ensuring that the results of experimental studies like this one can be translated into clinical applications,” concludes Dr. Fernández-Barrena.

Bibliographic reference
Cell Reports Medicine. 2026 Mar 31:102717. doi: 10.1016/j.xcrm.2026.102717. 
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