Control of T-cell stemness and T-cell exhaustion by KEAP1-NRF2 axis

In cancer and chronic infection, T cells develop into a dysfunctional state called exhaustion because of persistent antigen stimulation. Exhausted T cells upregulate immune checkpoints, display dysregulated metabolism, and progressively lose effector function and the ability to persist and develop immune memory. T cell exhaustion hinders the clearance of pathogens and malignant cells by the immune system and limits the effectiveness of immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. Therefore, understanding how T cells adapt to chronic antigen receptor signaling is critical for developing more effective immunotherapies. A stem-like CD8 T cell subset has been identified in chronic infections and cancers. Stem-like CD8 T cells mediate long-term immunity by self-renewal and replenishing other CD8 T cell subsets. Stem-like properties in T cells are essential for the efficacy of immunotherapies. We have identified key transcription factors that regulate the differentiation of stem-like CD8 T cells. However, the molecular program underlying the adaptation of stem-like CD8 T cells to chronic antigen receptor signaling is incompletely understood. Our recent findings show that the redox sensing KEAP1-NRF2 pathway is critical for the differentiation of stem-like CD8 T cells and adaptation of CD8 T cells to chronic antigen receptor signaling. In the proposed study, we will determine how the KEAP1-NRF2 pathway regulates the adaptation of CD8 T cells to persistent antigen receptor signaling through preventing TCR hyperactivation and promoting metabolic fitness. Our study will shed important new light on the development of more potent and efficacious immunotherapies for cancers and chronic infections. Furthermore, KEAP1 and NRF2 have been extensively investigated as potential drug targets for chronic diseases. Therefore, our findings hold significant promises for informing interventions that aim at modulating this pathway. Project Number: 1R01CA309621-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Chen Yao | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $402,011 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CDPT-C (08)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296819