Predictive biomarkers and preventive strategies for PTLD: a turning point in viro-immunologic precision medicine?

Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of complications with rising complexity, particularly as EBV-negative forms are increasingly recognized in adult recipients. While early EBV-driven PTLD was historically monitored by viral load, this approach fails to detect EBV-negative disease and lacks specificity even in EBV-positive cases. Recent advances in tumor immunology, virology, and liquid biopsy technologies have led to the emergence of novel biomarkers that offer improved diagnostic precision. These include plasma soluble ZEBRA antigen, reflecting lytic EBV activation; EBV DNA methylation status, which may distinguish latent from benign viral replication; and LMP1 sequence variants that influence immune evasion through the NKG2A/HLA-E axis. For EBV-negative PTLD, circulating tumor DNA profiling has shown promise for early, non-invasive detection. These innovations are complemented by preventive strategies such as anti-CD20 therapy in high-risk EBV-seronegative transplant recipients and ongoing trials of EBV-targeted vaccines. However, such approaches remain limited to EBV-naïve patients. Moving forward, integrating viral, immune, and tumor-derived markers—alongside host genetic factors—may enable more personalized surveillance and preemptive interventions. This review outlines the evolving paradigm of PTLD monitoring and highlights key areas where viro-immunologic precision medicine may reshape clinical practice.