Spi-B and IRF1 activate tumor immunogenicity downstream of the Epstein-Barr virus protein LMP1.

Low immunogenicity hinders antitumor immunity and causes resistance to immunotherapies in solid tumors. We previously reported that enforced expression of latent membrane protein 1 (LMP1), encoded by the Epstein-Barr virus, enhances the immunogenicity of B cells and triggers immune surveillance while driving their transformation. Here, we demonstrate that LMP1 transduction markedly upregulates MHC class I and co-stimulatory molecules in multiple solid tumor cell lines, enabling CD8+ T cell activation. LMP1 promotes the presentation of endogenous retroviral elements, allowing T cells to eliminate tumor cells, irrespective of LMP1 expression. Mechanistically, we identify the transcription factors Spi-B and IRF1 as key regulators of the immunostimulatory process of LMP1. Furthermore, the co-expression of Spi-B and IRF1 in solid tumor cells elicits robust CD8+ T cell responses and suppresses tumor growth in vivo. These findings uncover a transcriptional axis that activates antigen-presenting functions in solid tumor cells, offering a strategy to overcome immunotherapy resistance.