GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE318nnn/GSE318203/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE318203GEOGSEfalseNR2F6 Functions as a Key Transcriptional Checkpoint Enforcing Dysfunction of Human CD3+ T cells and Limiting CAR-T Cell PotencyAlthough NR2F6 regulates lymphocyte activation in murine models, its function in human T cells remains incompletely defined. Here, we identify NR2F6 as a TCR inducible transcriptional checkpoint that limits effector potency in human CD3⁺ T cells, including chimeric antigen receptor (CAR) T cells. In an anti EGFR CAR T cell-A549 co culture model, enforced NR2F6 expression, mimicking its upregulation in tumor infiltrating lymphocytes, markedly impairs killing under repeated tumor challenge. In polyclonal T cells, NR2F6 overexpression and CRISPR/Cas9-mediated ablation produced directionally opposing effects, supporting its role as a negative regulator of activation, differentiation-associated programs, and cytokine production. Mechanistically, transcriptomic, epigenomic, and nuclear protein analyses are consistent with suppression of NFAT , AP 1 , and NF κB-associated pathways and reveal context dependent changes in TCF 1-associated readouts. Collectively, these findings position NR2F6 as a signaling integrated transcriptional checkpoint that contributes to dysfunctional T cell states and may promote tumor immune evasion in humans.2026/09/09GSE318203GSM9489213GSM9489202GSM9489212GSM9489201GSM9489211GSM9489200GSM9489210GSM9489199GSM9489198GSM9489197GSM9489209GSM9489219GSM9489208GSM9489207GSM9489218GSM9489206GSM9489217GSM9489216GSM9489205GSM9489215GSM9489204GSM9489203GSM948921434284318203Homo sapiens