Characterizing resistant cellular states in nasopharyngeal carcinoma during EBV lytic induction

The pervasive occurrence of nasopharyngeal carcinoma (NPC) is intricately linked to Epstein-Barr virus (EBV) infection, making EBV and its associated pathways promising therapeutic targets for NPC and other EBV-related cancers. Lytic induction therapy, an emerging virus-targeted therapeutic strategy, capitalizes on the presence of EBV in tumor cells to specifically induce cytotoxicity against EBV-associated malignancies. Despite the expanding repertoire of compounds designed to induce EBV lytic reactivation, achieving universal induction across all infected cells remains elusive. The inherent heterogeneity of tumor cells likely contributes to this variability. In this study, we used a recently generated EBV-positive NPC cell line, named NPC43, as the in vitro model for NPC, and employed single-cell transcriptomics to delineate the diverse responses of NPC43 cells to lytic induction of EBV. Our longitudinal monitoring revealed a distinctive lytic induction non-responsive cellular state characterized by elevated expression of SOX2 and NTRK2. Cells in this state exhibit phenotypic similarities to cancer stem cells (CSCs), and we verified the roles of SOX2 and NTRK2 in manifesting these phenotypes. This discovery underscores a limitation in lytic induction efficacy, suggesting that not all tumor cells are susceptible to this treatment, highlighting the importance of integrating lytic induction with other targeted approaches during therapy.