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<sup>+</sup> T cell anti-tumor responses is fundamental. Here, we show that the transcription factor Helios is induced in tumor-infiltrating CD8<sup>+</sup> T cells in human and murine cancer. Genetic deletion of Helios in CD8<sup>+</sup> T cells reduces tumor growth, decreases the number of intratumoral terminally exhausted CD8<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Rosa Maria Rubio
- Florencia Rosetti (ORCID: https://orcid.org/0000-0001-7270-4515)
- José C. Crispín (ORCID: https://orcid.org/0000-0002-7590-3621)
- Cristina Aguilar-Flores (ORCID: https://orcid.org/0000-0001-5317-4731)
- Enrique Soto‐Pérez‐de‐Celis (ORCID: https://orcid.org/0000-0002-7301-2163)
- Saraí G De León-Rodríguez (ORCID: https://orcid.org/0000-0002-2451-0123)
- Marco Antonio Fonseca-Montaño (ORCID: https://orcid.org/0000-0002-5992-6989)
- Laura C. Bonifaz (ORCID: https://orcid.org/0000-0001-8482-5648)
- Iris K. Madera‐Salcedo (ORCID: https://orcid.org/0000-0002-0741-9248)
- Adrián Albarrán‐Godínez
- Laura Gómez-Romero (ORCID: https://orcid.org/0000-0001-9685-6492)
- Marysol González‐Yáñez
- Fernando Candanedo-González (ORCID: https://orcid.org/0000-0002-6926-8182)
- Gerardo Suárez‐Rojas (ORCID: https://orcid.org/0000-0002-4861-8569)
- Michelle Téllez-Sütterlin (ORCID: https://orcid.org/0009-0005-9708-6588)
- David Cortez (ORCID: https://orcid.org/0000-0003-0154-140X)
- Sofia V de Los Santos-Carmona
- Karla Guzmán-Barrenechea
Institutions
- Mexican Social Security Institute (MX)
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX)
- Centro Medico Nacional Siglo XXI (MX)
- Universidad Nacional Autónoma de México (MX)
- Tecnológico de Monterrey (MX)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116680
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00