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Small-molecule control of CAR T cells

Nature Reviews Chemistry volume 9, pages 809–825 (2025)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T cell therapy is a ‘living drug’ in which the T cells of patients are genetically engineered with an artificial receptor that directs them to attack diseased cells. CAR T cell therapies have had remarkable impact, curing subsets of patients with previously untreatable, late-stage cancers. However, limitations persist, including severe toxicities, limited survival of engineered cells, and therapeutic resistance. Genetically encoded small-molecule control systems have been developed to address these limitations. They can halt toxicities by eliminating CAR T cells or switching off their function. Furthermore, they can enhance therapy by directly targeting antigens or broadening cell killing ability through cytotoxic pro-drug activation. Small-molecule controllers include protease inhibitors, protein dimerizers, protein degraders, bi-specific adaptors and conditionally activated chemotherapeutics. Here, we outline small-molecule-based control approaches, categorizing them by function and detailing their molecular mechanisms. We emphasize systems in the clinic and highlight emerging applications and unmet areas.

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Fig. 1: Introduction to CAR T cells, shortcomings and small-molecule control solutions.
Fig. 2: Chemical structures of small molecules used to control CAR T cells.
Fig. 3: Small-molecule approaches to eliminate CAR T cells.
Fig. 4: Small-molecule control mechanisms of CAR presence and assembly.
Fig. 5: Antigen targeting of universal CAR T cells by small-molecule adaptors.
Fig. 6: Strategies to control accessory genes and cytotoxic pro-drug activation.

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Acknowledgements

This work was supported by NIH grants R01 GM142007 (to J.L. and A.D.), R01 CA290866 (to J.L. and A.D.) and T32 EB001026 (to V.S.).

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  1. These authors contributed equally: Eric L. Adams, Andrew C. McGovern.

Authors and Affiliations

  1. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Eric L. Adams, Andrew C. McGovern, Victor So, Sneha Srinivasan & Jason Lohmueller

  2. Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Eric L. Adams, Andrew C. McGovern, Victor So, Sneha Srinivasan & Jason Lohmueller

  3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Eric L. Adams, Andrew C. McGovern, Victor So, Sneha Srinivasan & Jason Lohmueller

  4. Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Eric L. Adams, Victor So, Alexander Deiters & Jason Lohmueller

  5. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Alexander Deiters

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Contributions

All authors researched data for the article and contributed substantially to discussion of the content. E.L.A., A.C.M., V.S., A.D. and J.L. wrote the article. A.C.M., V.S., A.D. and J.L. reviewed and edited the manuscript before submission.

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Correspondence to Alexander Deiters or Jason Lohmueller.

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Competing interests

J.L. and A.D. have personal financial interests in the form of stocks in the privately traded company Monarch Therapeutics, LLC. They are also inventors on patent applications filed by the University of Pittsburgh (J.L.: US11117936B2, awarded, mSA2-CAR technology; J.L. and A.D.: WO2020072764A, pending, SNAP-CAR technology; J.L. and A.D.: WO2022099065A, pending, conditional adaptor switches; J.L. and A.D.: 63/541,954, pending, small-molecule adaptors). Aspects of WO2020072764A are licensed by Coeptis Therapeutics, and aspects of WO2020072764A, US11117936B2, WO2022099065A and 63/541,954 are licensed by Monarch Therapeutics.

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Nature Reviews Chemistry thanks Kui Cheng, Michael Traxlmayr, Elise Sylvander and Dhruv K. Sethi for their contribution to the peer review of this work.

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Adams, E.L., McGovern, A.C., So, V. et al. Small-molecule control of CAR T cells. Nat Rev Chem 9, 809–825 (2025). https://doi.org/10.1038/s41570-025-00768-6

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