Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition
Abstract
:1. Introduction
γδ T-Cell Subset | Paired Vγ Gene Usage | Distribution | Features | Tumor-Related Functions | References |
Vδ1+T cells | Vγ2/3/4/5/8/9 | PB, skin, gut, Spleen, liver | Express NK cell receptors, Toll-like receptors, co-stimulatory factors; exhibit cytotoxicity against tumor cells via IFN-γ, and IL-10; low levels of IL-4, perforin, and granzyme | 1. Promote tumor growth by secreting cytokines like IL-17 that induce vascular endothelial growth factor (VEGF) secretion from tumor cells 2. Antitumor effect: In some hematological malignancies (such as leukemia), the clonal expansion and cytotoxicity of adult Vδ1 cells may enhance the tumor-killing ability, which is associated with a better prognosis | [18,19,20,21,22,23] |
Vδ2+T cells | Vγ9 | PB | Mainly Vγ9Vδ2 T cells responding to phosphorylated non-peptide “PAgs”; categorized into subgroups based on CD27 and CD45RA expression; naive and central memory cells respond to isopentenyl pyrophosphate (IPP), effector memory cells produce high IFN-γ, and terminally differentiated cells secrete perforin and granzyme | Effector memory Vδ2+ T cells have strong antitumor capacity, while terminally differentiated cells exert cytotoxic effects; activated Vδ2+ T cells can serve as antigen-presenting cells (APCs) | [24,25,26,27] |
Vδ3+T cells | Vγ2/3 | PB, liver | Express CD56, CD161, NKG2D; enhance CD1d recognition and act on CD1d target cells expressing CD107a | Limited investigations: functional role in tumor-related studies is not well defined | [28,29] |
Vδ5+T cells | Vγ4 | PB | EPCR | [16] | |
Functional Subsets | Source | Secreted Cytokines | Function | References | |
IFN-γ+ γδ T cell | thymus origin | IFN-γ | Functionally diverse: autoimmune diseases and tumor surveillance | [30] | |
IL-17+ γδ T cell | Vδ1γδ T-cell subpopulation of thymus origin | IL-17; | Rapid induction of IL-8-mediated migration and phagocytosis of neutrophils | [31] | |
γδ Treg | Vδ1γδ T-cell subpopulation | IFN-γ; GM-CSF | Inhibitory effect on the proliferation of autologous innate CD4+T cells | [32] | |
γδ T-APC | Initiated a specific immune response | [13] | |||
TIGIT + γδ T | Vδ1γδ T cells | Dysfunctional effector state | [33] |
2. Mechanisms Underlying Tumor Cell Recognition and the Stimulation of γδ T Cells
2.1. Early Studies on γδ T-Cell Activation: The Initial Discovery of PAgs
Name | Specific Source | Biological Activity | Research Progress | References |
---|---|---|---|---|
TUBag4 | Mycobacterium tuberculosis H37RV strain | Stimulates Vγ9Vδ2 T cell expansion supports the hypothesis of γδ T cell recognition of non-peptide ligands | First isolated from M. tuberculosis, confirming non-peptide ligands can activate Vγ9Vδ2 T cells. | [9] |
IPP | Tumor cells, bacteria (e.g., Mycobacterium smegmatis), eukaryotic mevalonate pathway | Weak agonist requires higher concentrations to activate Vγ9Vδ2 T cells | Natural intermediate of MVP in eukaryotic cells, increased expression in tumor cells. | [12] |
DMAPP | Tumor cells, bacteria, eukaryotic mevalonate pathway | Weak agonist, similar to IPP, requires higher concentrations to activate Vγ9Vδ2 T cells | Like IPP, an intermediate of MVP, increased expression in tumor cells. | [12] |
HMBPP | Bacteria (e.g., E. coli, M. tuberculosis), parasites (e.g., Plasmodium) via MEP pathway | Strongest natural agonist, activates Vγ9Vδ2 T cells at very low concentrations | In 2023, its hydroxyl group was found to form hydrogen bonds with BTN3A1, explaining its high potency. | [17] |
BrHPP | Synthetic compound (modified from natural phosphoantigen structures) | Highly efficient synthetic activator, activity close to HMBPP | Widely used in clinical research as a substitute for HMBPP. | [11] |
Zoledronic Acid (ZOL) | Synthetic amino bisphosphonate (originally developed for osteoporosis treatment) | Indirectly activates Vγ9Vδ2 T cells by inhibiting the MVP pathway and increasing IPP levels | Used in immunotherapy, confirming its immunomodulatory effects. | [43] |
Pamidronate | Synthetic amino bisphosphonate | Indirectly activates Vγ9Vδ2 T cells by inhibiting the MVP pathway and increasing IPP levels | Similar to ZOL, it is used in cancer treatment research. | [44] |
2.2. How γδ T Cells Detect PAg: BTN3A Family
2.3. Various Factors Induce Changes in Cell Membrane Fluidity
2.4. BTN2A1 Serves as a Direct Ligand for Vγ9Vδ2 T Cells
3. The Two-Fold Function of γδ T Cells in the TME
3.1. The Direct Antitumor Effect of γδ T Cells
3.2. Coordination of Additional Cells by γδ T Cells in Antitumor Activity
3.3. The Promoting Effect of γδ T Cells on Tumors
3.4. Coordination of Additional Cells by γδ T Cells in Promoting Tumors
4. Immunotherapy with γδ T Cells
Subset | Tumor Type | Function and Prognostic Association | Role in TME | Potential Therapeutic Strategies | References |
---|---|---|---|---|---|
Vδ1+ γδ T Cells | Colorectal Cancer | Poor prognosis (MSS type): this comprises 74.4% of γδ T cells with impaired function (reduced levels of cytotoxic molecules such as perforin, granzyme B, and IFN-γ). | Inflammatory fibroblasts overexpress NECTIN2, which binds to TIGIT on Vδ1+ cells, thereby suppressing their activity. | Anti-TIGIT antibodies or NECTIN2 blockade. | [84] |
Favorable prognosis (MSI type): maintains strong cytotoxicity (granzyme B and IFN-γ). | Direct tumor cell killing. | PD-1 inhibitors are effective, but only in a minority of cases. | [84] | ||
Non-Small Cell Lung Cancer | Favorable prognosis: high abundance of intratumoral Vδ1+ T cells is associated with recurrence-free survival. TCGA data indicate a longer overall survival in patients with high TRDV1 expression. | CD103+ Vδ1+ T cells colonize lung tissue and recognize early tumor stress signals independent of MHC restriction. | Expand CD103+ Vδ1+ T cells ex vivo for adoptive transfer to enhance tumor targeting. | [21] | |
Merkel Cell Carcinoma | 1. Enriched in MHC-I-deficient tumors, compensating for CD8+ T cell limitations. 2. Vδ1+ clonal expansion correlates with prolonged survival. | 1. NKG2D-mediated killing of MHC-I-deficient tumors. 2. Direct recognition of MCPyV viral peptides via TCR. | Design MCPyV peptide vaccines to enhance Vδ1+ T cell expansion. | [106] | |
Ovarian Cancer | CD3+Vδ1+ T cells are significantly elevated in ovarian cancer patients and correlate with advanced FIGO stage and metastasis. | High Foxp3 and Vδ1 expression, low CD28, maintaining immunosuppressive function and promoting progression. | Target Vδ1+ surface markers (e.g., Vδ1, Foxp3) to block immunosuppression. | [107] | |
Hepatocellular Carcinoma (HCC) | 1. Increased Vδ1+/Vδ2+ ratio correlates with shorter survival. 2. CD69+ Vδ1+ T cells are antitumor subpopulations linked to smaller tumor size and prolonged survival. | 1. Synergizes with apoptosis, ferroptosis, and pyroptosis pathways; PD-1/PD-L1 overexpression. 2. CD69+ Vδ1+ T cells localize to tumor sites for direct cytotoxicity. | 1. Combine PD-1/PD-L1 inhibitors to reverse T cell exhaustion. 2. Expand CD69+ Vδ1+ T cells ex vivo for adoptive transfer. | [108,109] | |
Vδ2+ γδ T Cells | Renal Cell Carcinoma | No direct prognostic correlation, but γδ T cell models (including Vδ2) predict immunotherapy response. | Functionally restricted in high TGF-β or IL-10 environments; requires combination therapy. | Zoledronic acid or BTN3A1 agonists to enhance activity. | [110] |
Colon Adenocarcinoma | Vδ2+ infiltration correlates with inflammation but lacks standalone prognostic value. | Activity depends on tumor BTN3A1 expression and phosphoantigen availability; suppressed in TGF-β-rich TME. | Pre-treat tumor cells with zoledronic acid to increase IPP release and activate Vδ2+ cells. | [111] | |
Breast Cancer | Reduced peripheral Vδ2+ T cell levels correlate with tumor progression. | Vγ9Vδ2 TCR recognizes tumor metabolic stress via BTN3A1. | Adoptive transfer of ex vivo-expanded Vδ2+ cells combined with IL-2 to sustain activity. | [112] | |
Ovarian Cancer | No significant difference in CD3+Vδ2+ T cell proportions between benign and malignant tumors. | Likely not directly involved in immunosuppression. | Not recommended as a therapeutic target. | [107] | |
Multiple Myeloma | Reduced peripheral Vδ2+ T cells correlate with advanced disease; bone marrow Vδ2+ T cell infiltration links to relapse/refractory MM. | CXCL10 recruits γδ T cells via CXCR3 into hypoxic bone marrow, promoting IL-17+ polarization. | Restore Vδ2+ function with PD-1 inhibitors combined with SRC-3 inhibitors. | [113] |
4.1. Research on BTN3A1 and Vγ9Vδ2 T-Cell Immunotherapy
4.2. Types of Immunotherapeutic γδ T Cells
Clinical Trials Gov Identifier | Interventions | Cancers/Tumors | Phase | Outcomes/Preliminary Findings |
---|---|---|---|---|
Autologous/Allogeneic γδ T cells | ||||
NCT02418481 | γδ T cells with or without DC-CIK cells | Breast Cancer | I/II | No published results (Study Completion June 2016). |
NCT02425735 | Vγ9Vδ2 T cells with or without DC-CIK cells | Cholangiocarcinoma | I/II | Modulated immune functions, reduced tumor activity, enhanced quality of life, and extended lifespan. Following eight γδ T cell treatments, there was a significant reduction in lymph node size along with diminished activity [123]. |
NCT02425748 | γδ T cells with or without DC-CIK cells | Lung Cancer | I/II | No published results (Study Completion 20 June 2019). Offer another promising immunotherapy approach. |
NCT02585908 | Vγ9Vδ2 T cells with or without CIK cells | Gastric Cancer | I/II | No published results (Study Completion December 2022). |
NCT03180437 | Vγ9Vδ2 T cells with IRE surgery | Locally Advanced Pancreatic Cancer | I/II | Strengthened immune response, inhibited tumor expansion, and prolonged the survival of liver and pancreas cancer patients [139]. |
NCT03183232 | γδ T cells with Cryosurgery or IRE | Liver Cancer Lung Cancer | I/II | Decreased tumor volume and increased survival in mice. Allogeneic Vγ9Vδ2 T cells have shown clinical safety and initial evidence of therapeutic effectiveness in patients with solid tumors [122]. |
NCT03533816 | Ex-vivo Expanded/Activated γδ T-cell Infusion | Hematological Malignancies | I | Assessing the maximum tolerated dose and safety profile of autologous gamma-delta T cells in leukemia patients who have undergone a partially matched bone marrow transplant. |
NCT03790072 | Ex-vivo Expanded Allogeneic γδ T-lymphocytes (OmnImmune®) | Acute Myeloid Leukemia | I | Allogeneic Vγ9Vδ2 T-cell infusion was shown to be safe and feasible up to a cell dose of 108/kg [140]. |
NCT04764513 | Ex-vivo expanded γδ T-cell infusion | Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndromes Lymphoma | I/II | Recruiting (Study Completion December 2025). |
NCT04518774 | Ex-vivo expanded Allogeneic γδ T cells | Hepatocellular Carcinoma | Early Phase I | No published results (Study Completion 15 August 2021). |
NCT04696705 | Ex-vivo expanded Allogeneic γδ T cells | Non-Hodgkin’s Lymphoma and Peripheral T-Cell Lymphomas | Early phase I | No published results (Study Completion 25 December 2023). |
NCT04765462 | Allogeneic γδ T cells | Malignant Solid Tumors | I/II | No published results (Study Completion 31 December 2024). |
NCT05015426 | γδ T-Cell Infusion | Acute Myeloid Leukemia | I | Not Recruiting (Study Completion September 2026). |
NCT05358808 | Ex-Vivo expanded Allogeneic γδ T-lymphocytes (TCB008) | Acute Myeloid Leukemia Myelodysplastic Syndromes | II | Recruiting (Study Completion December 2025). |
NCT05628545 | Allogeneic γδ-T Cells (GDKM-100) | Advanced Hepatocellular Carcinoma | I/II | No published results (Study Completion 31 October 2024). |
NCT05886491 | Allogeneic Vδ1 T cells | Acute Myeloid Leukemia | I/II | Recruiting (Study Completion 30 June 2027). |
CAR-γδ T cell | ||||
NCT02656147 | Anti-CD19-CAR-γδ T cell | Leukemia and Lymphoma | I | No published results (Study Completion April 2020). |
NCT04107142 | NKG2DL-targeting CAR-γδ T cell | Solid Cancer | I | NKG2DL-targeting CAR-γδ T cells enhanced cytotoxicity against tumor cell lines, with Vγ9Vδ2 T cells modified by NKG2D RNA-based CAR showing notable therapeutic effects in mouse tumor models [141]. |
NCT04702841 | CAR-γδ T cell | Relapsed and Refractory CD7 positive T | I | No published results (Study Completion December 2022). |
NCT04735471/ NCT04911478/ NCT06375993 | ADI-001 Anti-CD20 CAR-engineered Allogeneic γδ T Cells | Lymphoma, Follicular Lymphoma, Mantle-Cell Marginal Zone Lymphoma Primary Mediastinal B-cell Lymphoma/Lupus Nephritis Autoimmune Diseases | I | CD20 CAR-modified Vδ1 γδ T cells did not cause xenogeneic graft-versus-host disease in immunodeficient mice. They demonstrated tumor cell lysis in vitro and proinflammatory cytokine release, as well as inhibition of B-cell lymphoma xenograft growth in immunodeficient mice [142]. |
NCT05388305 | CAR-γδ T cell | Acute myeloid leukemia | Not applicable | No published results (Study Completion 30 May 2023). |
NCT05302037 | Allogeneic NKG2DL-targeting CAR-grafted γδ T cells (CTM-N2D) | Malignancy Refractory Cancer | I | Recruiting (Study Completion December 2026). |
NCT05554939 | Allogeneic CD19-CAR-γδ T cell | Non-Hodgkin’s Lymphoma | I/II | Recruiting (Study Completion 31 December 2026). |
NCT05653271 | Allogeneic CD20-conjugated γδ T-cell | B-cell Lymphoma Non-Hodgkin’s Lymphoma Primary Mediastinal Large B Cell Lymphoma | I | Recruiting (Study Completion September 2027). |
NCT06106893 | CD19 Universal CAR-γδ T cells | Systemic Lupus Erythematosus | I/II | Recruiting (Study Completion December 2027). |
NCT06150885 | CAR-γδ T cells CAR001 | Solid Tumor | I/II | Recruiting (Study Completion 30 September 2027). |
NCT06404281 | γδ T-PD-1 Ab cells | Advanced Solid Tumors | I | Recruiting (Study Completion 1 June 2026). |
NCT06480565 | ADI-270 (engineered γδ Chimeric Receptor CAR Vδ1 T cells Targeting CD70) | Clear Cell Renal Cell Carcinoma | I/II | Recruiting (Study Completion June 2027). |
Antibodies with Autologous/Allogeneic γδ T cells | ||||
NCT04243499 | Anti-BTN3A | Hematological and Solid Ttumors | I/II | Good tolerability and pharmacodynamic activity in initial patients, with the potential to enhance immune cell infiltration into the tumor microenvironment [8]. |
NCT06364800 | Allogeneic γδ T cells combined with targeted therapy and PD-1 | Hepatocellular Carcinoma | Early Phase 1 | Recruiting (Study Completion 26 September 2026). |
NCT06212388 | Allogeneic γδ T cells Combined with Interferon-alpha1b or PD-1 | Melanoma | Early Phase 1 | Recruiting (Study Completion 30 October 2028). |
Drug with Autologous/Allogeneic γδ T cells | ||||
NCT04165941 | Drug Resistant Immunotherapy with Activated, Gene-Modified γδ T cells | Glioblastoma Multiforme | I | Increased median survival in mice [143]. |
NCT05400603 | Ex Vivo Expanded Allogeneic γδ T cells in Combination with Dinutuximab, Temozolomide, Irinotecan, and Zoledronate | Neuroblastoma Refractory Neuroblastoma Relapsed Neuroblastoma Relapsed Osteosarcoma Refractory Osteosarcoma | I | Recruiting (Study Completion December 2025). |
NCT05664243 | Gene-Modified Allogeneic or Autologous γδ T cells | Glioblastoma | I/II | Recruiting (Study Completion December 2025). |
NCT06364787 | Allogeneic Gamma-delta T cells combined with targeted therapy and immunotherapy | Hepatocellular Carcinoma | I | Recruiting (Study Completion September 2026). |
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
PAg | Phosphoantigen |
MVP | Mevalonate pathway |
BTN3A1 | Butyrophilin Subfamily 3 Member A1 |
BTN2A1 | Butyrophilin Subfamily 2 Member A1 |
TME | Tumor microenvironment |
MHC | Major histocompatibility complex |
αβT | Alpha-Beta T |
γδ T | Gamma-Delta T |
TCR | T Cell Receptor |
VEGF | Vascular endothelial growth factor |
GM-CSF | Granulocyte-Macrophage Colony-Stimulating Factor |
IPP | Isopentenyl Pyrophosphate |
APCs | Antigen-Presenting Cells |
DMAPP | Dimethylallyl Pyrophosphate |
HMBPP | Hydroxymethylbutenyl Diphosphate |
HMGR | 3-Hydroxy-3-Methylglutaryl-CoA Reductase |
MEP | methylerythritol phosphate pathway |
β2M | β2-microglobulin |
JM | juxtamembrane |
NK cell | Natural killer cell |
DC | Dendritic cell |
TAAs | Tumor-associated antigens |
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Tang, J.; Wu, C.; Na, J.; Deng, Y.; Qin, S.; Zhong, L.; Zhao, Y. Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition. Curr. Oncol. 2025, 32, 329. https://doi.org/10.3390/curroncol32060329
Tang J, Wu C, Na J, Deng Y, Qin S, Zhong L, Zhao Y. Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition. Current Oncology. 2025; 32(6):329. https://doi.org/10.3390/curroncol32060329
Chicago/Turabian StyleTang, Jing, Chen Wu, Jintong Na, Yamin Deng, Simin Qin, Liping Zhong, and Yongxiang Zhao. 2025. "Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition" Current Oncology 32, no. 6: 329. https://doi.org/10.3390/curroncol32060329
APA StyleTang, J., Wu, C., Na, J., Deng, Y., Qin, S., Zhong, L., & Zhao, Y. (2025). Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition. Current Oncology, 32(6), 329. https://doi.org/10.3390/curroncol32060329