The transcription factor Helios restrains the anti-tumor capacity of CD8⁺ T cells

Immunotherapy has revolutionized cancer treatment, but it lacks efficacy in a sizable fraction of patients. Therefore, understanding the transcriptional networks that limit CD8⁺ T cell anti-tumor responses is fundamental. Here, we show that the transcription factor Helios is induced in tumor-infiltrating CD8⁺ T cells in human and murine cancer. Genetic deletion of Helios in CD8⁺ T cells reduces tumor growth, decreases the number of intratumoral terminally exhausted CD8⁺ T cells, and increases the frequency of cells with a transcriptional profile indicative of progenitor capacity. These changes are associated with increased chromatin accessibility in loci encoding stemness-related genes. The combination of Helios and PD-1 deficiencies robustly improves the anti-tumoral capacity of CD8⁺ T cells. A Helios inhibitor, identified in a small-molecule screen, improves the anti-tumoral effects of PD-1 deficiency. These results demonstrate that Helios represents a therapeutic target that can boost anti-cancer immunotherapy.