Marco Ongaro, Romane Thouenon, Isaac Crespo, Alexandre Dumez, Mélanie Charmoy, Eduardo Roman Camacho, Victoria J. Morel, Daniela Cropp, Emma Desponds, Giulio Zanette, Yi-Chuan Wang, Letizia Vergili, Laure Tillé, I. Resta, M.M. Leblond, Jesús Corría-Osorio, Ping‐Chih Ho, Werner Held, Grégory Verdeil
T cell exhaustion is a major obstacle to effective immunotherapy in cancer and chronic infection. Here, we identify the transcription factor IRF8 as a tumor-specific regulator of CD8+ T cell exhaustion. IRF8 is strongly expressed in tumor-reactive CD8+ T cells but not during chronic viral infection. Its expression is induced by TCR signaling and can be suppressed by type I IFN (IFN-I). Sustained IFN-I signaling, a hallmark of chronic infection, correlates with reduced chromatin accessibility at the Irf8 locus and progressive repression of Irf8 expression. In tumor-specific CD8+ T cells, IRF8 overexpression enhanced TOX expression while reducing IFNγ, granzyme B, and TNF production. Conversely, Irf8 deficiency diminished exhaustion, restored effector functions, and improved tumor control. Mechanistically, IRF8 directly binds the Tox locus and promotes its transcription. We further show that additional IRF-family transcription factors contribute similarly to the exhausted T cell program, identifying this transcriptional network as a key regulator of tumor-associated T cell dysfunction.