Recombining domains across an entire protein family, rather than relying on natural sequences shaped by evolution, generates synthetic “DESynR” transcription factors with enhanced function. DESynR AP-1 TFs reprogram CAR T cells into non-natural, therapeutically optimized states and outperform natural AP-1 factors in antitumor immunity.

Nature Cancer, Published online: 05 March 2026; doi:10.1038/s43018-026-01135-0Dong and colleagues report that blockade of T cell-expressed cytotoxic and regulatory T cell molecule results in selective mitigation of immune-related toxicities without affecting antitumor efficacy of immune checkpoint inhibitors.