A protein-engineering platform that creates artificial transcription factors by recombining domains from naturally occurring proteins improved the antitumor performance of CAR-T cells in preclinical models, according to a study published August 19, 2026 in Cell. The approach allows researchers to screen thousands of non-natural regulatory programs for combinations that make therapeutic T cells more resistant to exhaustion.
The work, led by researchers including Ansuman Satpathy at Stanford University and Theodore Roth, now faculty at Stanford and the University of California, San Francisco, addresses T-cell exhaustion — the progressive loss of function caused by persistent antigen stimulation that remains a major obstacle to durable CAR-T activity, particularly in solid tumors.
The DESynR (Domain Engineered via Synthesis and Recombination) platform treats transcription factors as modular proteins whose functional domains can be separated and recombined. Rather than overexpressing or removing a single naturally occurring regulator, the researchers shuffled domains from the AP-1, ETS, and FOX transcription-factor families to create libraries containing tens of thousands of synthetic proteins, which were then screened in primary human T cells under repeated antigen stimulation.
One of the strongest hits, JUN-FOS-BATF, combined domains from three different AP-1 family proteins. CAR-T cells expressing the synthetic transcription factor maintained greater cytotoxic activity following repeated stimulation than cells expressing the natural transcription factors tested or control CAR-T cells. They also retained higher proportions of stem-like and central memory T cells and showed lower expression of exhaustion-associated markers including PD-1, TIM-3, and LAG-3.
In immunodeficient mice bearing Nalm6 tumors, JUN-FOS-BATF-engineered CAR-T cells reduced tumor burden and prolonged survival compared with conventional CAR-T cells and cells engineered with natural AP-1 transcription factors. The effect was not confined to a single CAR target: leading DESynR constructs improved T-cell function across CD19-, GD2-, and NY-ESO-1-directed systems and in both CD4-positive and CD8-positive human T cells. The mouse studies were small, however, with approximately three to nine animals per treatment group.
Genomic analyses suggested that the synthetic factors created regulatory states difficult to achieve by manipulating individual natural transcription factors. JUN-FOS-BATF increased expression of genes associated with cytotoxicity and T-cell stemness while suppressing exhaustion-associated programs. The engineered cells did not show autonomous proliferation or antigen-independent activation in the absence of target cells, although substantially more safety testing would be required before broadly reprogrammed T cells could enter clinical development.