Diffuse large B-cell lymphoma (DLBCL), when associated with Epstein-Barr virus (EBV) in immunocompromised individuals such as AIDS patients, presents a significant treatment challenge. Lytic induction therapy, which reactivates latent EBV to directly kill tumor cells and sensitize them to nucleoside analogs that block viral replication and immune clearance, offers promise. However, little is known about EBV reactivation in DLBCL. Here, we examined four EBV-positive DLBCL cell lines and found variable, cell-line-specific responses to lytic stimuli, with most showing an abortive response-either before or after genome replication, without virus release. This is in contrast to commonly studied lymphoma cells in which EBV reactivation typically leads to a full lytic cycle. Mechanistically, we show that the unfolded protein response (UPR), via a splice variant of the transcription factor XBP1, upregulates TXNIP and NLRP3, activating the inflammasome and removing a barrier to transcription of the EBV latent-to-lytic switch gene BZLF1. Combining lytic induction with the nucleoside analog ganciclovir enhanced oncolytic cell death. This study identifies a pivotal link between two danger sensing pathways, the UPR and the inflammasome, in reactivating the virus resident in DLBCL and suggests that controlled lytic reactivation could provide a basis for EBV-targeted therapies to improve outcomes in this malignancy.
© The Author(s) 2025. Published by Oxford University Press on behalf of NAR Cancer.