Oncogenic Potential of Epstein‐Barr Virus in NK and NKT Cells Contribute to the Rapid Deterioration of Hemophagocytic Lymphohistiocytosis

The rapid deterioration and fatal outcomes in Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) remain poorly understood. This study aimed to elucidate the key factors contributing to the progression of EBV-HLH by comparing EBV cellular tropism and host immune responses between survivors and deceased patients. Compared to healthy individuals, acute HLH patients exhibited impaired natural killer (NK) cell activity, which improved during the recovery phase. However, deceased patients demonstrated heightened NK cell activity and increased EBV loads during the deterioration phase. Additionally, deceased patients had elevated EBV-specific T cell responses without cytokine storm, suggesting other factors beyond host immunity contribute to HLH deterioration. Notably, in deceased cases, EBV infection spread to NK and NKT cells with a highly proliferative profile, whereas it was limited to B cells in survivors. Furthermore, EBV-infected NK and NKT cells displayed a higher percentage of copy number variations and significant enrichment in canonical cancer pathways compared to noninfected cells, indicating their oncogenic potential and possible contribution to HLH deterioration. These findings provide insights into the pathogenesis of EBV-HLH and may guide the development of targeted therapeutic strategies.