A New Approach to Improving Immunotherapy for Liver Cancer

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

Researchers from the Hepatgroup at Cima of Navarra have identified a new strategy that could improve the effectiveness 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 internship, 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 co-directors of the study.

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

A 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 cells), thereby improving the response to immunotherapy, which is not very effective on its own. This approach particularly important in a tumor such as liver cancer, where clinical experience indicates that the response to immunotherapy remains limited.”

This work , conducted at the Cancer Center at the Clínica Universidad de Navarra, opens up a new avenue for improving the treatment of liver cancer by combining 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 effectiveness of current treatments.”

The collaborative study was conducted within the framework CIBEREHD (research center network Liver and Digestive Diseases) and involved several leading national and international groups in the field of hepatology. It has 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 association Against Cancer and the “la Caixa” Foundation.

“The partnership efforts of all the groups involved have been essential in ensuring that the results of programs of study like this one can be translated into clinical practice,” concludes Dr. Fernández-Barrena.

reference letter bibliographic

Cell Reports Medicine. March 31, 2026:102717. doi: 10.1016/j.xcrm.2026.102717.
• Inhibition of histone methyltransferase G9a boosts the efficacy of immune checkpoint inhibitors in experimental hepatocellular carcinoma