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Integrated in vivo and multiparameter in vitro screen uncovers NFIL3 as driver of T cell dysfunction

GSE313731 Homo sapiens Expression profiling by high throughput sequencing; Other 6 samples Submitted 2026/02/19 Platform GPL24676
Summary
CAR therapy has transformed the treatment landscape for hematological malignancies but its efficacy in solid tumors is limited, owing in part to insufficient functional persistence of the engineered T cells. To elucidate the basis for their functional decline, we conducted a multi- parameter in vivo discovery screen of 400 transcription factors, which revealed NFIL3 as a driver of CAR T cell dysfunction. Genetic disruption of NFIL3 in CAR T cells sustained their expansion, increased cytokine production, overall restraining terminal differentiation. Loss of NFIL3 enhances CAR T cell efficacy, improving tumor control and prolonging survival in xenograft and syngeneic mouse tumor models across different CAR designs. Under chronic stimulation, disruption of NFIL3 establishes a transcriptional state predictive of favorable clinical outcomes. Our findings underscore the power of comprehensive multi-parameter genetic screens conducted in vivo and reveal NFIL3 as a novel therapeutic target to enhance cancer immunotherapy.
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Also filed as BioProject PRJNA1381500 and SRA study SRP655197. Searching any of these in the dataset finder brings you back here.

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