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Background CAR-T cells have shown remarkable clinical success in treating relapsed/refractory hematologic malignancies, and CAR-T cell therapy is being avidly pursued for treatment of solid tumors. However, loss of full-range of T cell function over time (exhaustion), and impaired CAR-T persistence remain key challenges that limit the therapeutic potential in solid tumors. T cells are hardwired to pursue a natural path of differentiation, unless nudged via transcriptional modification of the activation and exhaustion program. We hypothesized that introducing noises in the gene network early during T cell programming, via targeted transcriptional engineering, can lead to divergent fates of CAR T cells in solid tumors. This can modify their natural susceptibility for exhaustion and enhance their responsiveness to checkpoint blockade immunotherapy.Methods We used an immunocompetent solid tumor model to understand the role of chronic CAR signaling on exhaustion and trajectory modification using transcriptional engineering. ID3 and ID2 and reciprocal regulators of T cell fate. We ectopically expressed ID3 in CAR T cells to modify their fate towards precursor stem-like progenitor cells.Results Using an immunocompetent preclinical model of CAR-T therapy of melanoma, here we show that ectopic expression of the pro-memory transcription factor Inhibitor of DNA binding 3 (Id3) in CAR T cells (Id3-CAR) augments durable solid tumor control in vivo, which lasted up to the lifespan of the mice. Augmented in vivo tumor control by the pro-memory transcription factor Id3 was associated with sustained cytotoxicity and serial tumor killing in vitro, robust production of effector cytokines (IFN-α and TNF-α), as well as increased intra-tumoral localization of the transcriptionally engineered CAR T cells. Id3-CAR T cells preferentially differentiated into TCF-1Hi stem-like cells compared to WT-CAR T cells, with higher expression of memory-associated markers (such as Bcl-2, IL-7Rα and CD62L), lesser terminal exhaustion and displayed enhanced responsiveness to checkpoint blockade.Conclusions We show that transcriptional engineering of CAR T cells has the power to modify the lineage fate of CAR T cells in solid tumors and lead to better tumor control. Mechanistically, it leads to less exhausted CAR T cells, better persistence and enhanced responsiveness to checkpoint blockade immunotherapy. These data highlight Id3 and other such pro-memory transcription factors as attractive CAR engineering targets to bypass exhaustion in the TME, enhance PD-1 therapy outcomes and promote durable CAR T cell memory and protection from tumor relapse.