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Disrupting the balance between activating and inhibitory receptors of γδT cells for effective cancer immunotherapy

Nature Reviews Cancer volume 25, pages 590–612 (2025)Cite this article

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Abstract

γδT cell biology in cancer has been studied for decades but remains poorly understood mainly due to species differences in preclinical models and a lack of appropriate analytical tools. This lack of knowledge has hindered the clinical translation of promising therapeutic concepts. In recent years, advanced single-cell analysis techniques and comprehensive protein–protein interaction studies have transformed our understanding of γδT cells and their receptors. This insight has revealed new opportunities and challenges in harnessing γδT cells for therapeutic purposes. In this context, we will discuss the latest findings in γδT cell biology, with a special focus on their role in cancer immune therapies. We will explore strategies to overcome tolerance and shift the balance of γδT cells and their receptors towards antitumour efficacy, which has the potential to successfully translate into various engineering approaches in cancer immunotherapy.

Key points

  • Vγ9Vδ2 γδT cells and Vδ2– γδT cells have distinct transcriptomic profiles and different therapeutic potential in cancer therapy.

  • The unique γδT cell receptor–CD3 complex structure and its downstream signalling pathways have implications for the design of effective therapeutics.

  • Shifting the equilibrium between activating and inhibitory receptors is essential for the clinical success of both γδT cell-based biologics and engineered T cells.

  • Biomimetic models and Good Manufacturing Practice simulation will be necessary to accelerate the development process.

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Fig. 1: Regulation of BTN2A1 and BTN3A expression and metabolic alterations are required for Vγ9Vδ2 γδT cell activation.
Fig. 2: Structures of γδTCRs in complex with their cognate ligand or CD3 complex reveal a diversity of unique and unexpected topologies.
Fig. 3: Diverse activation mechanisms of γδT cells.
Fig. 4: Metabolic challenges of γδT cells in cancer.
Fig. 5: Therapeutic strategies to break the balance between activating and inhibitory receptors of γδT cells to improve therapeutic efficacy.
Fig. 6: Biomimetic models and GMP simulation are key elements for rapid clinical translation of γδT cell-based therapies.

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Acknowledgements

Funding for this study was provided by Dutch Cancer Society (KWF: 12586, 13043, 13493, 15614, 15570) and KIKA473 to J.K. National Growth Fund Oncode Accelerator (https://www.oncodeaccelerator.nl) provided support to J.K., Z.S., T.S. and D.X.B. S.M. is supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy – EXC-2189 Project ID: 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 (MI1942/3-1), SFB1479 (project ID: 441891347 - P15), SFB1160 (project ID: 256073931 - B01), and projects MI1942/4-1 (project ID: 501418856) and MI1942/5-1 (project ID: 501436442). S.M. is also supported by the Dutch Cancer Society (KWF project ID: 13043). T.S. is supported by grants provided by the Dutch Cancer Society (KWF: 12586 and 13876) and National Growth Fund RegMed XB pilot Factory UMCU Innovation Center of Advanced Therapies. D.X.B. is supported by a grant provided by the Dutch Cancer Society (KWF: 15570).

Author information

Authors and Affiliations

  1. Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    Dennis X. Beringer, Trudy Straetemans, Caterina Riillo, Zsolt Sebestyen & Jürgen Kuball

  2. Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands

    Trudy Straetemans & Jürgen Kuball

  3. Signalling Research Centres BIOSS and CIBSS, Freiburg, Germany

    Susana Minguet

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

    Susana Minguet

  5. Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Susana Minguet

  6. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Lydia Lynch

  7. Ludwig Cancer Research Institute, Princeton Branch, Princeton, NJ, USA

    Lydia Lynch

Authors
  1. Dennis X. Beringer
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  2. Trudy Straetemans
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  3. Susana Minguet
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  4. Caterina Riillo
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  5. Lydia Lynch
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  6. Zsolt Sebestyen
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  7. Jürgen Kuball
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Contributions

All authors researched data for the article. D.X.B., T.S., S.M., L.L., C.R., Z.S. and J.K. contributed substantially to discussion of the content. All authors wrote the article. D.X.B., Z.S., S.M. and J.K. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Jürgen Kuball.

Ethics declarations

Competing interests

J.K. was a shareholder of Gadeta and is a shareholder of Gadeta Founder BV. J.K., Z.S., L.L. and D.X.B. are inventors on patents with γδTCR-related topics. J.K., Z.S. and D.X.B. are inventors on patents with CD277-related topics. L.L. is on the SAB of MiNK Therapeutics, Faeth Therapeutics and Deciduous Therapeutics. All other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Michal Besser who co-reviewed with Ilan Bank, Mary Poupot and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Innovation Center for Advanced Therapies (ICAT): https://icat-utrecht.nl/en

Glossary

Activation-induced cell death

Apoptosis of T cells due to strong or prolonged activation of the T cell receptor.

Advanced therapy medicinal products

(ATMPs). Innovative medical therapies based on engineered genes, cells or tissue designed to treat or prevent disease.

Aminobisphosphonates

(NBPs). A nitrogen-containing class of drugs that inhibits the mevalonate pathway, leading to an accumulation of phosphoantigens in tumour cells.

Biomimetic models

Artificial systems or structures designed to imitate biological processes, functions or materials found in nature. These models are used in research and development to study complex biological phenomena, develop new technologies or create therapeutic solutions.

Bispecific T cell engagers

(TCEs). Engineered molecules designed to simultaneously bind to a specific protein on tumour cells and to another protein, normally CD3, on T cells. This dual binding directs the T cells to attack and destroy the cancer cells.

Chimeric antigen receptors

(CARs). Genetically engineered receptors that enhance the capacity of immune effector cells to recognize and kill specific cancer cells.

Clonal expansion

The rapid proliferation of genetically identical T cells from a single parental cell, enhancing the immune response to specific pathogens or abnormal cells.

Complementarity-determining region

(CDR). Specific portion of the variable regions of an antibody or T cell receptor that determines antigen-binding specificity.

CRISPR–Cas9

Genome-editing technology that uses a guide RNA to direct the Cas9 nuclease to specific DNA sequences creating double-strand breaks for precise gene modification.

Cryo-electron microscopy

Technique that captures high-resolution images of biological samples cooled at cryogenic temperature, preserving their native structure.

Cytokine release syndrome

Rapid release of cytokines by immune effector cells caused by immunotherapy treatment, leading to systemic inflammation.

Exhaustion

A dysfunctional state of immune cells caused by chronic exposure to antigen and characterized by increased inhibitory receptor expression and reduced effector function.

Fab

Antibody fragment consisting of variable heavy and first constant heavy domains paired with variable light and constant light domains that binds to antigens.

Functional avidity

The capability of a specific T cell receptor (TCR) to activate T cell functions, such as cytotoxicity, cytokine secretion and proliferation, as a function of ligand concentration. A TCR with high functional avidity is capable of activating T cells at low ligand concentrations.

Glutamine

Most abundant amino acid in the serum essential for T cell activation, proliferation, cytokine production and nucleotide synthesis.

Graft-versus-host

The reactivity of transplanted donor-derived immune cells to healthy cells of the recipient.

Graft-versus-leukaemia

The reactivity of transplanted donor-derived immune cells to leukaemia cells in the patient.

Immune effector cell-associated neurotoxicity syndrome

A common adverse event after immunotherapy affecting neurological functions, caused by inflammation in the central nervous system.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). Highly conserved regions located in the cytoplasmic tail of immune receptors, crucial for conveying activation signals in immune cells.

Lipidome

The complete array of lipids within a biological system representing its metabolic state and function.

Mevalonate pathway

Essential metabolic pathway for the synthesis of important molecules like cholesterol, ubiquinone and dolichol. The enzymes of the mevalonate pathway are frequently overexpressed and highly active in cancer cells, leading to the promotion of tumour growth. One of the central metabolites in the mevalonate pathway is isopentenyl pyrophosphate, the key endogenous phosphoantigen required for Vγ9Vδ2T cell activation.

Nanoparticles

Ultra-small particles, ranging from 1 to 100 nm, characterized by unique physical and chemical properties.

Opsonins

Molecules that enhance the process of phagocytosis by tagging pathogens or cells for recognition by the immune system.

Phosphoantigens

(pAg). Metabolites containing a pyrophosphate group, such as isopentenyl pyrophosphate, dimethylallyl pyrophosphate and (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, and sensed by BTN2A1 and BTN3A, which subsequently induce Vγ9Vδ2T cell activation.

Post-marketing authorization studies

Also known as post-authorization safety studies; clinical studies carried out after a drug has received marketing authorization in order to acquire additional safety and/or efficacy data or to evaluate the effectiveness of risk management measures.

Purine synthesis

A biosynthesis pathway for purine molecules essential for the synthesis of adenine and adenosine monophosphate and guanine and guanosine monophosphate.

Pyroglutamate

A post-translational modification of an N-terminal glutamine of a protein, where the side chain of glutamine reacts with a free amino group, resulting in the cyclic amino acid pyroglutamate. Several enzymes can catalyse this reaction, for example, glutaminyl-peptide cyclotransferase-like protein in the Golgi apparatus and glutaminyl-peptide cyclotransferase in the extracellular space.

Shedding

Highly regulated proteolytic release of extracellular domains of membrane proteins from the cell surface into the surrounding environment.

Single-chain variable fragment

(ScFv). Fusion protein composed of the variable heavy and light chains of immunoglobulins connected by a short linker.

Single nucleotide polymorphisms

Genetic variation involving a change in a single nucleotide in the DNA sequence, potentially influencing phenotypic characteristics or disease susceptibility.

Superantigen

Superantigens are a class of pathogen-derived proteins that bind to TCRs outside of their conventional recognition sites, such as the CDRs, triggering a polyclonal T cell response.

T cell repertoires

Diverse and unique arrays of TCRs present in an individual, enabling the detection of a broad range of antigens.

TCR constant domains

Extracellular membrane-proximal domains of the TCR not involved in antigen recognition. αβTCR constant domains interact with the extracellular domains of CD3, whilst γδTCR constant domains have no interaction with the extracellular domains of CD3.

TCR variable domains

Extracellular membrane distal domains of the TCR important for antigen binding and specificity through their highly variable CDR loops.

Tonic signalling

A sustained, non-specific activation of T cells that occurs independently of ligand binding.

Tumour organoids

3D cell cultures derived from patient tumour samples that recapitulate the complexity of the structure and function of the original tumour.

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Beringer, D.X., Straetemans, T., Minguet, S. et al. Disrupting the balance between activating and inhibitory receptors of γδT cells for effective cancer immunotherapy. Nat Rev Cancer 25, 590–612 (2025). https://doi.org/10.1038/s41568-025-00830-x

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