Human induced pluripotent stem cell (iPS cell)-derived chimeric antigen receptor (CAR) T cells hold great therapeutic potential, but often present an immature phenotype compared with αβ T cells used for autologous CAR T cell therapy. A new study shows that H3K9-directed histone methyltransferases G9a–GLP inhibition enables the generation of mature iPS cell-derived T cells.

Jing et al. performed a chemical screen and multiple functional experiments using a stroma-free human iPS cell–T cell differentiation protocol and found that UNC0224, an inhibitor of the histone lysine methyltransferase G9a–GLP complex, enhances the commitment of haematopoietic stem and progenitor cells into lymphoid fates. Chromatin accessibility and transcriptomics analyses indicated that G9a–GLP regulates lymphoid genes. Importantly, Jing et al. then showed that UNC0224 treatment increased the iPS cell-derived mature CD8α+CD8β+αβTCR+ T cells and their transcriptional resemblance to peripheral blood T cells. Finally, experiments including a xenograft tumour model indicated that CAR T cells produced upon UNC0224 treatment achieve higher tumour clearance and improve survival.