Researchers have identified a potential new treatment approach for Epstein-Barr virus–positive (EBV+) gastric cancer, a subtype marked by extreme DNA hypermethylation that shuts down tumor-suppressor genes.
In this cancer type, the virus triggers a process called CpG Island Methylator Phenotype (CIMP). This adds methyl groups to DNA, acting like an “off switch” that silences genes that would normally slow tumor growth or help the immune system recognize cancer cells.
To reverse this effect, researchers used decitabine (DCB), an FDA-approved drug that blocks DNA methylation. DCB removes methyl groups and reopens previously silenced regions of DNA. The study found that the retinoic acid (RA) signaling pathway, which is strongly suppressed in EBV+ tumors, could be reactivated after treatment. DCB partially restored the activity of RA receptors such as RARα and RARβ, making cancer cells responsive again to all-trans retinoic acid (ATRA), a vitamin A–based cancer therapy.
The researchers propose combining DCB with ATRA as a two-step strategy. First, DCB increases the production of reactive oxygen species (ROS) by boosting enzymes such as NOX5 and DUOX1/2, creating internal oxidative stress in cancer cells. At the same time, reactivated RA signaling weakens the cell’s antioxidant defense system, particularly the NRF2 pathway, preventing the tumor from clearing the toxic ROS. As oxidative stress builds up, the cancer cells undergo programmed cell death.
The treatment response was much stronger in EBV+ gastric cancer cells than in EBV-negative cells, suggesting the strategy is subtype-specific. The study also identified biomarkers such as HOPX, a gene found at low levels in EBV+ tumors but reactivated by DCB. In addition, DCB triggered the virus’s lytic phase, marked by expression of the Zta protein, which could create further therapeutic opportunities.
Overall, the findings suggest that targeting epigenetic silencing with a DCB and ATRA combination may offer a promising new strategy for EBV-positive gastric cancer.