Reprogramming CAR T-Cells with designed bioPROTACs

2026 · doi:10.64898/2026.02.21.706835
preprint OA: closed
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Designed bioPROTACs can be expressed in CAR T-cells to target and degrade DNMT3A, mimicking gene knockout and providing a tunable, reversible strategy to reprogram T-cell fate without gene editing.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-17 · read from full text ⓘ

The paper studies whether de novo designed bioPROTACs—targeted protein degraders expressed in CAR T-cells—can reprogram CAR T-cell function without gene editing. CAR T-cells targeting DNMT3A (a regulator implicated in T-cell exhaustion) were engineered to express bioPROTACs, and the resulting cellular changes phenocopied those achieved by DNMT3A knockout. The key caveat stated is that this is a non-gene-editing, reversible approach rather than a permanent genetic disruption, which may limit direct comparison to gene-editing strategies. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

ABSTRACT Gene editing has been used to enhance CAR T-cell function by disrupting negative regulators but has limitations. Here we show that de novo-designed generated targeted degraders (bioPROTACs) provide an alternative approach. Expression of bioPROTACs in CAR T-cells targeting DNMT3A, a key regulator of T-cell exhaustion, phenocopied gene knockout. Our reversible, non-gene editing approach provides a tunable strategy to reprogram T-cell fate which should be broadly applicable for next-generation cell therapies.
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ABSTRACT Gene editing has been used to enhance CAR T-cell function by disrupting negative regulators but has limitations. Here we show that de novo-designed generated targeted degraders (bioPROTACs) provide an alternative approach. Expression of bioPROTACs in CAR T-cells targeting DNMT3A, a key regulator of T-cell exhaustion, phenocopied gene knockout. Our reversible, non-gene editing approach provides a tunable strategy to reprogram T-cell fate which should be broadly applicable for next-generation cell therapies. Competing Interest Statement VSP, SK, TGK, LW, RET, BY, DB, SG have patents or patent applications in the fields of cell or gene therapy. SG is a member of the Scientific Advisory Board of Be Biopharma and the Data and Safety Monitoring Board (DSMB) of Immatics. BC, TM, IG, MGS, RM, MS, DV, RK, YK, Z-FY, AH, AN, EW, AA, FF, TC declare no competing interests. Footnotes ↵# These authors share senior authorship

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last seen: 2026-05-20T01:45:00.602351+00:00