Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity

Taisuke Kondo¹, François X P Bourassa², Sooraj Achar³, Justyn DuSold¹, Pablo F Céspedes⁴, Makoto Ando¹, Alka Dwivedi¹, Josquin Moraly¹, Christopher Chien¹, Saliha Majdoul¹, Adam L Kenet⁵, Madison Wahlsten⁵, Audun Kvalvaag⁶, Edward Jenkins⁷, Sanghyun P Kim⁸, Catherine M Ade⁸, Zhiya Yu⁸, Guillaume Gaud⁹, Marco Davila¹⁰, Paul Love⁹, James C Yang⁸, Michael L Dustin⁷, Grégoire Altan-Bonnet¹¹, Paul François¹², Naomi Taylor¹³

Affiliations

¹ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
² Department of Physics, McGill University, Montréal, QC, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.
³ Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁴ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; CAMS Oxford Institute, University of Oxford, Oxford, UK.
⁵ Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁶ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
⁷ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁸ Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁹ Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
¹⁰ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹¹ Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: gregoire.altan-bonnet@nih.gov.
¹² Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada; MILA Québec, Montréal, QC, Canada. Electronic address: paul.francois@umontreal.ca.
¹³ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Université de Montpellier, Institut de Génétique Moléculaire de Montpellier, Montpellier, France. Electronic address: taylorn4@mail.nih.gov.

PMID: 40220754
PMCID: PMC12107475 (available on 2026-05-01)
DOI: 10.1016/j.cell.2025.03.017

Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity

Taisuke Kondo et al. Cell. 2025.

. 2025 May 1;188(9):2372-2389.e35.

doi: 10.1016/j.cell.2025.03.017. Epub 2025 Apr 11.

Authors

Affiliations

¹ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
² Department of Physics, McGill University, Montréal, QC, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.
³ Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁴ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; CAMS Oxford Institute, University of Oxford, Oxford, UK.
⁵ Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁶ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
⁷ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
⁸ Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁹ Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
¹⁰ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹¹ Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: gregoire.altan-bonnet@nih.gov.
¹² Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada; MILA Québec, Montréal, QC, Canada. Electronic address: paul.francois@umontreal.ca.
¹³ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Université de Montpellier, Institut de Génétique Moléculaire de Montpellier, Montpellier, France. Electronic address: taylorn4@mail.nih.gov.

PMID: 40220754
PMCID: PMC12107475 (available on 2026-05-01)
DOI: 10.1016/j.cell.2025.03.017

Abstract

Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHAT^L8F/p53^R175H) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.

Keywords: CAR T cells; TCR; cancer immunotherapy; fuzzy logic; humanized in vivo toxicity model; on-target/off-tumor toxicity; robotics; systems immunology; theoretical modeling.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity

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Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity

Authors

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Abstract

Conflict of interest statement

References

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