Enhancing the potency of CAR-T cells against solid tumors through transcription factor engineering

Transcription factors (TFs) play a pivotal role in the development and differentiation of T cells. Recent studies have highlighted unique transcriptional profiles in chimeric antigen receptor T (CAR-T) cells derived from patients with favorable clinical outcomes, suggesting a potential link between TF modulation and improved therapeutic efficacy. Although CAR-T cell therapies have shown some success in treating hematological malignancies, they are limited by challenges such as poor persistence, functional exhaustion, and tumor resistance. To overcome these limitations, researchers have attempted to enhance the efficacy of CAR-T cells through manipulation of TF expression. This Review provides a comprehensive overview of TF engineering in CAR-T cells and elucidates the complex regulatory network between TFs. Notably, modification of basic leucine zipper ATF-like transcription factor in CAR-T cells results in contradictory functional outcomes in different studies. We summarize the potential factors leading to such results and elucidate the importance of setting up a relevant in vitro model to evaluate the effect of TFs on CAR-T cells. In conclusion, this Review highlights the latest advances in TF modifications and proposes strategies for harnessing these insights to empower CAR-T cells with superior antitumor efficacy.