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  • Perspective
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From TCR fundamental research to innovative chimeric antigen receptor design

Nature Reviews Immunology volume 25, pages 212–224 (2025)Cite this article

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Abstract

Engineered T cells that express chimeric antigen receptors (CARs) have transformed the treatment of haematological cancers. CARs combine the tumour-antigen-binding function of antibodies with the signalling functions of the T cell receptor (TCR) ζ chain and co-stimulatory receptors. The resulting constructs aim to mimic the TCR-based and co-receptor-based activation of T cells. Although these have been successful for some types of cancer, new CAR formats are needed, to limit side effects and broaden their use to solid cancers. Insights into the mechanisms of TCR signalling, including the identification of signalling motifs that are not present in the TCR ζ chain and mechanistic insights in TCR activation, have enabled the development of CAR formats that outcompete the current CARs in preclinical mouse models and clinical trials. In this Perspective, we explore the mechanistic rationale behind new CAR designs.

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Fig. 1: The TCR and its functional signalling motifs.
Fig. 2: Different CAR formats.
Fig. 3: TCR-like chimeric receptors.
Fig. 4: Timeline of the development of CARs and TCR-like chimeric receptors.

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Acknowledgements

The research groups of S.M. and W.W.S. are supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy (EXC-2189 project 390939984) and under the Excellence Initiative of the German Federal and State Governments (EXC-294) and in part by the Ministry for Science, Research and Arts of the State of Baden-Württemberg. Further support is given by the DFG under FOR2799 (SCHA976/8-2 to W.W.S. and MI1942/3-1 to S.M.), SFB1381 (project 403222702-A9 to W.W.S.), SFB1479 (project 441891347-P15 to S.M.), SFB1160 (project 256073931-B01 to S.M.), and projects MI1942/4-1 (project 501418856 to S.M.) and MI1942/5-1 (project 501436442 to S.M.).

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Authors and Affiliations

  1. Signalling Research Centers BIOSS and CIBSS, Freiburg, Germany

    Susana Minguet & Wolfgang W. Schamel

  2. Department of Synthetic Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany

    Susana Minguet

  3. Centre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Susana Minguet & Wolfgang W. Schamel

  4. Cellular Immunotherapy Program and Krantz Family Center for Cancer Research, Mass General Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Marcela V. Maus

  5. Department of Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany

    Wolfgang W. Schamel

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S.M. and W.W.S. contributed equally to all aspects of the article. All authors wrote, reviewed and edited the manuscript before submission.

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Correspondence to Susana Minguet or Wolfgang W. Schamel.

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Competing interests

S.M. and W.W.S. are patent holders on ‘Lck-binding motif in CD3e’ (European patent application number 20711971.0 and US patent application number 20230070126). M.V.M. is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital and the University of Pennsylvania (some licensed to Novartis); holds equity in 2Seventy Bio, Genocea, Oncternal and Neximmune; and serves on the board of directors of 2Seventy Bio. W.W.S. and M.V.M. have served as consultants for multiple companies involved in cell therapies. The interests of M.V.M. were reviewed and are managed by Massachusetts General Hospital, and Massachusetts General Brigham in accordance with their conflict-of-interest policies.

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Minguet, S., Maus, M.V. & Schamel, W.W. From TCR fundamental research to innovative chimeric antigen receptor design. Nat Rev Immunol 25, 212–224 (2025). https://doi.org/10.1038/s41577-024-01093-7

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