γδ T cells in colorectal and liver cancer

γδ T cells in colorectal and liver cancer

  • Chien, Y. H., Meyer, C. & Bonneville, M. γδ T cells: first line of defense and beyond. Annu. Rev. Immunol. 32, 121–155 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pellicci, D. G., Koay, H. F. & Berzins, S. P. Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge. Nat. Rev. Immunol. 20, 756–770 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, S. W., Park, H. J., Van Kaer, L. & Hong, S. Role of CD1d and iNKT cells in regulating intestinal inflammation. Front. Immunol. 14, 1343718 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, Z., Chen, X., Han, F. & Leeansyah, E. MAIT cell homing in intestinal homeostasis and inflammation. Sci. Adv. 11, eadu4172 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beringer, D. X. et al. Disrupting the balance between activating and inhibitory receptors of γδT cells for effective cancer immunotherapy. Nat. Rev. Cancer 25, 590–612 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ribot, J. C., Lopes, N. & Silva-Santos, B. γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jameson, J. et al. A role for skin gammadelta T cells in wound repair. Science 296, 747–749 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nielsen, M. M., Witherden, D. A. & Havran, W. L. γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nat. Rev. Immunol. 17, 733–745 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bonneville, M., O’Brien, R. L. & Born, W. K. γδ T cell effector functions: a blend of innate programming and acquired plasticity. Nat. Rev. Immunol. 10, 467–478 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hu, Y. et al. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct. Target. Ther. 8, 434 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Parker, C. M. et al. Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J. Exp. Med. 171, 1597–1612 (1990).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wesch, D., Hinz, T. & Kabelitz, D. Analysis of the TCR Vgamma repertoire in healthy donors and HIV-1-infected individuals. Int. Immunol. 10, 1067–1075 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Perriman, L. et al. A three-stage developmental pathway for human Vγ9Vδ2 T cells within the postnatal thymus. Sci. Immunol. 8, eabo4365 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Deusch, K. et al. A major fraction of human intraepithelial lymphocytes simultaneously expresses the γ/δ T cell receptor, the CD8 accessory molecule and preferentially uses the Vδ1 gene segment. Eur. J. Immunol. 121, 1053–1059 (1991).

    Article 

    Google Scholar
     

  • Kenna, T. et al. Distinct subpopulations of γδ T cells are present in normal and tumor-bearing human liver. Clin. Immunol. 113, 56–63 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gray, J. I. et al. Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span. Sci. Immunol. 9, eadn3954 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kierkels, G. J. J. et al. Identification of a tumor-specific allo-HLA-restricted γδTCR. Blood Adv. 3, 2870–2882 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harly, C. et al. Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset. Blood 120, 2269–2279 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Herrmann, T. & Karunakaran, M. M. Phosphoantigen recognition by Vγ9Vδ2 T cells. Eur. J. Immunol. 54, e2451068 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Gruenbacher, G. & Thurnher, M. Mevalonate metabolism in immuno-oncology. Front. Immunol. 8, 1714 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roelofs, A. J. et al. Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br. J. Haematol. 144, 245–250 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Hintz, M. et al. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. FEBS Lett. 509, 317–322 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sandstrom, A. et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40, 490–500 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, L. et al. Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells. Nature 621, 840–848 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gu, S. et al. Phosphoantigen-induced conformational change of butyrophilin 3A1 (BTN3A1) and its implication on Vγ9Vδ2 T cell activation. Proc. Natl Acad. Sci. USA 114, E7311–E7320 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fulford, T. S. et al. Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers. Nat. Immunol. 25, 1355–1366 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Karunakaran, M. M. et al. A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing. Nat. Commun. 14, 7617 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rincon-Orozco, B. et al. Activation of Vγ9Vδ2 T cells by NKG2D. J. Immunol. 175, 2144–2151 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Toutirais, O. et al. DNAX accessory molecule-1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells. Eur. J. Immunol. 39, 1361–1368 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Silva-Santos, B. & Strid, J. Working in “NK mode”: natural killer group 2 member D and natural cytotoxicity receptors in stress-surveillance by γδ T cells. Front. Immunol. 9, 851 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cazzetta, V. et al. NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions. Cell Rep. 37, 109871 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dokouhaki, P. et al. NKG2D regulates production of soluble TRAIL by ex vivo expanded human γδ T cells. Eur. J. Immunol. 43, 3175–3182 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lettau, M. et al. Mechanistic peculiarities of activation-induced mobilization of cytotoxic effector proteins in human T cells. Int. Immunol. 30, 215–228 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sandoz, P. A. et al. Modulation of lytic molecules restrain serial killing in γδ T lymphocytes. Nat. Commun. 14, 6035 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Angelini, D. F. et al. FcγRIII discriminates between 2 subsets of Vγ9Vδ2 effector cells with different responses and activation pathways. Blood 104, 1801–1807 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Urban, E. M. et al. Control of CD56 expression and tumor cell cytotoxicity in human Vγ2Vδ2 T cells. BMC Immunol. 10, 50 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alexander, A. A. et al. Isopentenyl pyrophosphate-activated CD56 + γδ T lymphocytes display potent antitumor activity toward human squamous cell carcinoma. Clin. Cancer Res. 14, 4232–4240 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, D. et al. Unlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering. Nat. Commun. 14, 6942 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wesch, D., Glatzel, A. & Kabelitz, D. Differentiation of resting human peripheral blood γδ T cells toward Th1- or Th2-phenotype. Cell. Immunol. 212, 110–117 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Peters, C., Häsler, R., Wesch, D. & Kabelitz, D. Human Vδ2 T cells are a major source of interleukin-9. Proc. Natl Acad. Sci. USA 113, 12520–12525 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ness-Schwickerat, K. J., Jin, C. & Morita, C. T. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vγ2Vδ2 T cells. J. Immunol. 184, 7268–7280 (2010).

    Article 

    Google Scholar
     

  • Ribot, J. C. et al. CD27 is a thymic determinant of the balance between interferon-γ- and interleukin 17-producing γδ T cell subsets. Nat. Immunol. 10, 427–436 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Inácio, D. et al. Signature cytokine-associated transcriptome analysis of effector γδ T cells identifies subset-specific regulators of peripheral activation. Nat. Immunol. 26, 497–510 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duan, J., Chung, H., Troy, E. & Kasper, D. L. Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing γ/δ T cells. Cell Host Microbe 7, 140–150 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ribot, J. C., Ribeiro, S. T., Correia, D. V., Sousa, A. E. & Silva-Santos, B. Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. J. Immunol. 192, 2237–2243 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schilbach, K. et al. Suppressive activity of Vδ2+ γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength. Cancer Immunol. Immunother. 69, 593–610 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barjon, C. et al. IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population. Oncoimmunology 7, e1379642 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xia, C., Yin, S., To, K. K. W. & Fu, L. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol. Cancer 22, 44 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mao, Y. et al. A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells. Cell. Mol. Immunol. 13, 217–228 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chabab, G., Barjon, C., Bonnefoy, N. & Lafont, V. Pro-tumor γδ T cells in human cancer: polarization, mechanisms of action, and implications for therapy. Front. Immunol. 11, 2186 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harmon, C. et al. γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors. Nat. Cancer 4, 1122–1137 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kouakanou, L. et al. Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation. Sci. Rep. 10, 6550 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kabelitz, D., Serrano, R., Kouakanou, L., Peters, C. & Kalyan, S. Cancer immunotherapy with γδ T cells: many paths ahead of us. Cell. Mol. Immunol. 17, 925–939 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sebestyen, Z., Prinz, I., Déchanet-Merville, J., Silva-Santos, B. & Kuball, J. Translating gammadelta (γδ) T cells and their receptors into cancer cell therapies. Nat. Rev. Drug Discov. 19, 169–184 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mensurado, S., Blanco-Domínguez, R. & Silva-Santos, B. The emerging roles of γδ T cells in cancer immunotherapy. Nat. Rev. Clin. Oncol. 20, 178–191 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hayday, A., Dechanet-Merville, J., Rossjohn, J. & Silva-Santos, B. Cancer immunotherapy by γδ T cells. Science 386, eabq7248 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Arias-Badia, M., Chang, R. & Fong, L. γδ T cells as critical anti-tumor immune effectors. Nat. Cancer 5, 1145–1157 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Lv, J. et al. γδT cells, a key subset of T cell for cancer immunotherapy. Front. Immunol. 16, 1562188 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, Y. et al. An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Sci. Transl. Med. 11, eaax9364 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, H. et al. High abundance of intratumoral γδ T cells favors a better prognosis in head and neck squamous cell carcinoma: a bioinformatic analysis. Front. Immunol. 11, 573920 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, Y. et al. A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer. Nat. Cancer 3, 696–709 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, J. et al. Tumor-infiltrating γδT cells predict prognosis and adjuvant chemotherapeutic benefit in patients with gastric cancer. Oncoimmunology 6, e1353858 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gherardin, N. A. et al. γδ T cells in Merkel cell carcinomas have a proinflammatory profile prognostic of patient survival. Cancer Immunol. Res. 9, 612–623 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nguyen, S. et al. Vδ2 T cells are associated with favorable clinical outcomes in patients with bladder cancer and their tumor reactivity can be boosted by BCG and zoledronate treatments. J. Immunother. Cancer 10, e004880 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, C. et al. Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. J. Immunol. 189, 5029–5036 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, P. et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40, 785–800 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Patil, R. S. et al. IL17 producing γδT cells induce angiogenesis and are associated with poor survival in gallbladder cancer patients. Int. J. Cancer 139, 869–881 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Wu, Z. et al. Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing. Cell. Mol. Immunol. 21, 362–373 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mamedov, M. R. et al. CRISPR screens decode cancer cell pathways that trigger γδ T cell detection. Nature 621, 188–195 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gober, H. J. et al. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. 197, 163–168 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mattarollo, S. R., Kenna, T., Nieda, M. & Nicol, A. J. Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity. Cancer Immunol. Immunother. 56, 1285–1297 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wrobel, P. et al. Lysis of a broad range of epithelial tumour cells by human γδ T cells: involvement of NKG2D ligands and T-cell receptor- versus NKG2D-dependent recognition. Scand. J. Immunol. 66, 320–328 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mensurado, S. et al. CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells. Blood 143, 1488–1495 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mikulak, J. et al. NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI Insight 4, e125884 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Almeida, A. R. et al. Delta One T cells for immunotherapy of chronic lymphocytic leukemia: clinical-grade expansion/differentiation and preclinical proof of concept. Clin. Cancer Res. 22, 5795–5804 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Blanco-Domínguez, R. et al. Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer. Nat. Cancer 6, 1056–1972 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lockhart, A., Mucida, D. & Bilate, A. M. Intraepithelial lymphocytes of the Intestine. Annu. Rev. Immunol. 42, 289–316 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horn, V. & Sonnenberg, G. F. Group 3 innate lymphoid cells in intestinal health and disease. Nat. Rev. Gastroenterol. Hepatol. 21, 428–443 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Di Marco Barros, R. et al. Epithelia use butyrophilin-like molecules to shape organ-specific γδ T cell compartments. Cell 167, 203–218 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ullrich, R., Schieferdecker, H. L., Ziegler, K., Riecken, E. O. & Zeitz, M. gamma delta T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium. Cell. Immunol. 128, 619-627 (1990)

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Han, J. et al. TGF-β controls development of TCRγδ+CD8αα+ intestinal intraepithelial lymphocytes. Cell Discov. 9, 52 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suzuki, T., Hayman, L., Kilbey, A., Edwards, J. & Coffelt, S. B. Gut γδ T cells as guardians, disruptors, and instigators of cancer. Immunol. Rev. 298, 198–217 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dalton, J. E. et al. Intraepithelial γδ+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology 131, 818–829 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ismail, A. S. et al. γδ intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl Acad. Sci. USA 108, 8743–8748 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rampoldi, F. & Prinz, I. Three layers of intestinal γδ T cells talk different languages with the microbiota. Front. Immunol. 13, 849954 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Malinarich, F. H. et al. Constant TCR triggering suggests that the TCR expressed on intestinal intraepithelial γδ T cells is functional in vivo. Eur. J. Immunol. 40, 3378–3388 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Meehan, T. F. et al. Protection against colitis by CD100-dependent modulation of intraepithelial γδ T lymphocyte function. Mucosal Immunol. 7, 134–142 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, Y., Chou, K., Fuchs, E., Havran, W. L. & Boismenu, R. Protection of the intestinal mucosa by intraepithelial γδ T cells. Proc. Natl Acad. Sci. USA 99, 14338–14343 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Watanabe, M. et al. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J. Clin. Invest. 95, 2945–2953 (1995).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, Q. et al. MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8αα TCRαβ and TCRγδ intestinal intraepithelial lymphocytes. J. Immunol. 176, 6180–6185 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sullivan, Z. A. et al. γδ T cells regulate the intestinal response to nutrient sensing. Science 371, eaba8310 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xie, B. et al. Gut-derived memory γδ T17 cells exacerbate sepsis-induced acute lung injury in mice. Nat. Commun. 15, 6737 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, X. et al. Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nat. Immunol. 24, 625–636 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, G. Q. et al. The intestinal γδ T cells: functions in the gut and in the distant organs. Front. Immunol. 14, 1206299 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McCarthy, N. E. et al. Proinflammatory Vδ2+ T cells populate the human intestinal mucosa and enhance IFN-γ production by colonic αβ T cells. J. Immunol. 191, 2752–2763 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kyes, S., Carew, E., Carding, S. R., Janeway, C. A. Jr. & Hayday, A. Diversity in T-cell receptor gamma gene usage in intestinal epithelium. Proc. Natl Acad. Sci. USA 86, 5527–5531 (1989).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bas, A. et al. Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes. Proc. Natl Acad. Sci. USA 108, 4376–4381 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Melandri, D. et al. The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nat. Immunol. 19, 1352–1365 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jandke, A. et al. Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments. Nat. Commun. 11, 3769 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Panea, C. et al. Butyrophilin-like 2 regulates site-specific adaptations of intestinal γδ intraepithelial lymphocytes. Commun. Biol. 4, 913 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Willcox, C. R. et al. Butyrophilin-like 3 directly binds a human Vγ4+ T cell receptor using a modality distinct from clonally-restricted antigen. Immunity 51, 813–825 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McKenzie, D. R. et al. Normality sensing licenses local T cells for innate-like tissue surveillance. Nat. Immunol. 23, 411–422 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dart, R. J. et al. Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science 381, eadh0301 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rice, M. T. et al. Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor. Proc. Natl Acad. Sci. USA 118, e2110288118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wegrecki, M. et al. Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors. Nat. Commun. 13, 3872 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reijneveld, J. F. et al. Human γδ T cells recognize CD1b by two distinct mechanisms. Proc. Natl Acad. Sci. USA 117, 22944–22952 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morgan, E. et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 72, 338–344 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heregger, R. et al. Unraveling resistance to immunotherapy in MSI-high colorectal cancer. Cancers 15, 5090 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Corvaisier, M. et al. Vγ9Vδ2 T cell response to colon carcinoma cells. J. Immunol. 175, 5481–5488 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Maeurer, M. J. et al. Human intestinal Vdelta1 + lymphocytes recognize tumor cells of epithelial origin. J. Exp. Med. 183, 1681–1696 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Halary, F. et al. Shared reactivity of Vδ2neg γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells. J. Exp. Med. 201, 1567–1578 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Vries, N. L. et al. High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity. Gut 69, 691–703 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Meraviglia, S. et al. Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer. Oncoimmunology 6, e1347742 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rong, L. et al. Analysis of tumor-infiltrating gamma delta T cells in rectal cancer. World J. Gastroenterol. 22, 3573–3580 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rodin, W. et al. γδ T cells in human colon adenocarcinomas comprise mainly Vδ1, Vδ2, and Vδ3 cells with distinct phenotype and function. Cancer Immunol. Immunother. 73, 174 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chabab, G. et al. Diversity of tumor-infiltrating, γδ T-cell abundance in solid cancers. Cells 9, 1537 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, L. et al. Tumor-infiltrating gamma delta T-cells reveal exhausted subsets with remarkable heterogeneity in colorectal cancer. Int. J. Cancer 153, 1684–1697 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Karjalainen, H. et al. Characteristics and significance of γδ T cells in colorectal cancer. Oncoimmunology 14, 2532231 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yakou, M. H. et al. TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Sci. Immunol. 8, eadf2163 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stary, V. et al. Dysfunctional tumor-infiltrating Vδ1 + T lymphocytes in microsatellite-stable colorectal cancer. Nat. Commun. 15, 6949 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, X. et al. Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression. Exp. Cell Res. 386, 111719 (2010).

    Article 

    Google Scholar
     

  • Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, G. et al. Tumor-infiltrating CD39+γδ Tregs are novel immunosuppressive T cells in human colorectal cancer. Oncoimmunology 6, e1277305 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shida, D. et al. Prognostic value of primary tumor sidedness for unresectable stage IV colorectal cancer: a retrospective study. Ann. Surg. Oncol. 26, 1358–1365 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Zhan, Y. et al. PLA2G4A promotes right-sided colorectal cancer progression by inducing CD39 + γδ Treg polarization. JCI Insight 6, e148028 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suzuki, T. et al. β-Catenin drives butyrophilin-like molecule loss and γδ T-cell exclusion in colon cancer. Cancer Immunol. Res. 11, 1137–1155 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, X., Shan, Q. & Xue, H. H. TCF1 in T cell immunity: a broadened frontier. Nat. Rev. Immunol. 22, 147–157 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, K. et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41, 1052–1063 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, S. et al. IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 74, 1969–1982 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Housseau, F. et al. Redundant innate and adaptive sources of IL17 production drive colon tumorigenesis. Cancer Res. 76, 2115–2124 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jin, C. et al. Commensal microbiota promote lung cancer development via γδ T cells. Cell 176, 998–1013 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Begagic, E., Vranic, S. & Sominanda, A. The role of interleukin 17 in cancer: a systematic review. Carcinogenesis 46, bgae079 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reis, B. S. et al. TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets. Science 377, 276–284 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Amicarella, F. et al. Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut 66, 692–704 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ran, R., Trapecar, M. & Brubaker, D. K. Systematic analysis of human colorectal cancer scRNA-seq revealed limited pro-tumoral IL-17 production potential in gamma delta T cells. Neoplasia 58, 101072 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, A. Y., Wistuba-Hamprecht, K., Greten, T. F. & Ruf, B. Innate-like T cells in liver disease. Trends Immunol. 45, 535–548 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gao, B., Jeong, W. I. & Tian, Z. Liver: an organ with predominant innate immunity. Hepatology 47, 729–736 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14, 996–1006 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hu, Y. et al. Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells. Cell. Mol. Immunol. 18, 954–968 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Norris, S. et al. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J. Hepatol. 28, 84–90 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hunter, S. et al. Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations. J. Hepatol. 69, 654–665 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mangan, B. A. et al. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vδ3 T cells. J. Immunol. 191, 30–34 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hou, W. & Wu, X. Diverse functions of γδ T cells in the progression of hepatitis B virus and hepatitis C virus infection. Front. Immunol. 11, 619872 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ibidapo-Obe, O. & Bruns, T. Tissue-resident and innate-like T cells in patients with advanced chronic liver disease. JHEP Rep. 5, 100812 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Agrati, C. et al. Vδ1 T lymphocytes expressing a Th1 phenotype are the major γδ T cell subset infiltrating the liver of HCV-infected persons. Mol. Med. 7, 11–19 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, X. et al. Decreased Vδ2 γδ T cells associated with liver damage by regulation of Th17 response in patients with chronic hepatitis B. J. Infect. Dis. 208, 1294–1304 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, S. et al. Reciprocal alterations in circulating and hepatic gamma-delta T cells in patients with primary biliary cholangitis. Hepatol. Int. 16, 195–206 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2, 16018 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Sangro, B., Sarobe, P., Hervás-Stubbs, S. & Melero, I. Advances in immunotherapy for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 18, 525–543 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Di Blasi, D. et al. Unique T-cell populations define immune-inflamed hepatocellular carcinoma. Cell. Mol. Gastroenterol. Hepatol. 9, 195–218 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Cai, X. Y. et al. Low counts of γδ T cells in peritumoral liver tissue are related to more frequent recurrence in patients with hepatocellular carcinoma after curative resection. Asian Pac. J. Cancer Prev. 15, 775–780 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Zhao, N. et al. Intratumoral γδ T-cell infiltrates, chemokine (C-C motif) ligand 4/chemokine (C-C motif) ligand 5 protein expression and survival in patients with hepatocellular carcinoma. Hepatology 73, 1045–1060 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zakeri, N. et al. Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma. Nat. Commun. 13, 1372 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, H. et al. γδ T cells in hepatocellular carcinoma patients present cytotoxic activity but are reduced in potency due to IL-2 and IL-21 pathways. Int. Immunopharmacol. 70, 167–173 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yi, Y. et al. The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner. J. Hepatol. 58, 977–983 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xia, J., Wang, C. & Li, B. Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation. Front. Oncol. 14, 1451650 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, Y. et al. Apoptosis, pyroptosis, and ferroptosis conspiringly induce immunosuppressive hepatocellular carcinoma microenvironment and γδ T-cell imbalance. Front. Immunol. 13, 845974 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, W. et al. Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2+ γδ T cell can be a promising complement. Clin. Transl. Med. 12, e800 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • You, H. et al. CD69+ Vδ1γδ T cells are anti-tumor subpopulations in hepatocellular carcinoma. Mol. Immunol. 172, 76–84 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bruni, E. et al. Intrahepatic CD69+Vδ1 T cells re-circulate in the blood of patients with metastatic colorectal cancer and limit tumor progression. J. Immunother. Cancer 10, e004579 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bruni, E. et al. Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer. J. Immunother. Cancer 7, 347 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Handgretinger, R. & Schilbach, K. The potential role of γδ T cells after allogeneic HCT for leukemia. Blood 131, 1063–1072 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu, Y. et al. Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell. Mol. Immunol. 18, 427–439 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saura-Esteller, J. et al. Gamma delta T-cell based cancer immunotherapy: past-present-future. Front. Immunol. 13, 915837 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, D. et al. Ex vivo expanded human circulating Vδ1 γδT cells exhibit favorable therapeutic potential for colon cancer. Oncoimmunology 4, e992749 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Devaud, C. et al. Anti-metastatic potential of human Vδ1+ γδ T cells in an orthotopic mouse xenograft model of colon carcinoma. Cancer Immunol. Immunother. 62, 1199–1210 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Van Acker, H. H. et al. Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells. J. Hematol. Oncol. 9, 101 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aehnlich, P., Carnaz Simões, A. M., Skadborg, S. K., Holmen Olofsson, G. & Thor Straten, P. Expansion with IL-15 increases cytotoxicity of Vγ9Vδ2 T cells and is associated with higher levels of cytotoxic molecules and T-bet. Front. Immunol. 11, 1868 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fowler, D. et al. Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma. Sci. Transl. Med. 16, eadg9814 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nattress, C. B. et al. Phenoscaping reveals multimodal γδ T cell cytotoxicity as a strategy to overcome cancer cell-mediated immunomodulation. Cancer Res. 85, 4415–4432 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kouakanou, L. et al. Vitamin C promotes the proliferation and effector functions of human γδ T cells. Cell. Mol. Immunol. 17, 462–473 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Uslu, U. & June, C. H. Beyond the blood: expanding CAR T cell therapy to solid tumors. Nat. Biotechnol. 43, 506–515 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Thomas, P., Paris, P. & Pecqueur, C. Arming Vδ2 T cells with chimeric antigen receptors to combat cancer. Clin. Cancer Res. 20, 3105–3116 (2024).

    Article 

    Google Scholar
     

  • Zhai, X. et al. MUC1-Tn-targeting chimeric antigen receptor-modified Vγ9Vδ2 T cells with enhanced antigen-specific anti-tumor activity. Am. J. Cancer Res. 11, 79–91 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Makkouk, A. et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J. Immunother. Cancer 9, e003441 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Magee, M. S. et al. Human GUCY2C-targeted chimeric antigen receptor (CAR)-expressing T cells eliminate colorectal cancer metastases. Cancer Immunol. Res. 6, 509–516 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, M. et al. CD318 is a target of chimeric antigen receptor T cells for the treatment of colorectal cancer. Clin. Exp. Med. 23, 2409–2419 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • de Bruin, R. C. G. et al. A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells. Oncoimmunology 7, e1375641 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Diest, E. et al. Gamma delta TCR anti-CD3 bispecific molecules (GABs) as novel immunotherapeutic compounds. J. Immunother. Cancer 9, e003850 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Marcu-Malina, V. et al. Redirecting αβ T cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor. Blood 118, 50–59 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Straetemans, T. et al. GMP-grade manufacturing of T cells engineered to express a defined γδTCR. Front. Immunol. 9, 1062 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meringa, A. D. et al. Strategies to improve γδTCRs engineered T-cell therapies for the treatment of solid malignancies. Front. Immunol. 14, 1159337 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • De Gassart, A. et al. Development of ICT01, a first-in-class, anti-BTN3A antibody for activating Vγ9Vδ2 T cell-mediated antitumor immune response. Sci. Transl. Med. 13, eabj0835 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Champiat, S. et al. EVICTION study: ICT01, an anti-butyrophilin 3A monoclonal antibody activating γ9δ2 T cells in combination with pembrolizumab in checkpoint inhibitor refractory melanoma. J. Clin. Oncol. 42, 9534 (2024).

    Article 

    Google Scholar
     

  • Maiti, A. et al. ICT01, an investigational γ9δ2 T cell activator, added to azacitidine-venetoclax achieves frequent and early complete remissions in adults with AML unfit for intensive induction chemotherapy: interim results from the ongoing open-label, randomized phase 1 study eviction. Blood 144, 2876 (2024).

    Article 

    Google Scholar
     

  • Payne, K. K. et al. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells. Science 369, 942–949 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Todaro, M. et al. Efficient killing of human colon cancer stem cells by γδ T lymphocytes. J. Immunol. 182, 7287–7196 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zocchi, M. R. et al. Zoledronate can induce colorectal cancer microenvironment expressing BTN3A1 to stimulate effector γδ T cells with antitumor activity. Oncoimmunology 6, e1278099 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reid, I. R. et al. Zoledronate. Bone 137, 115390 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Di Mascolo, D. et al. Nanoformulated zoledronic acid boosts the Vδ2 T cell immunotherapeutic potential in colorectal cancer. Cancers 12, 104 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Benelli, R. et al. Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab. J. Immunother. Cancer 10, e005660 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tyler, C. J. et al. Antigen-presenting human γδ T cells promote intestinal CD4+ T cell expression of IL-22 and mucosal release of calprotectin. J. Immunol. 198, 3417–3425 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Holmen Olofsson, G. et al. Vγ9Vδ2 T cells concurrently kill cancer cells and cross-present tumor antigens. Front. Immunol. 12, 645131 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rancan, C. et al. Exhausted intratumoral Vδ2 γδ T cells in human kidney cancer retain effector function. Nat. Immunol. 24, 612–624 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Davies, D. et al. PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy. Nat. Cancer 5, 420–432 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Vries, N. L. et al. γδ T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 613, 743–750 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, H. et al. B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells. Oncoimmunology 9, 1748991 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • André, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mantovani, A., Allavena, P., Marchesi, F. & Garlanda, C. Macrophages as tools and targets in cancer therapy. Nat. Rev. Drug Discov. 21, 799–820 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wesch, D., Kabelitz, D. & Oberg, H. H. Tumor resistance mechanisms and their consequences on γδ T cell activation. Immunol. Rev. 298, 84–98 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, Q., Yu, M. & Zhang, S. The characteristics of the tumor immune microenvironment in colorectal cancer with different MSI status and current therapeutic strategies. Front. Immunol. 15, 1440830 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shen, K. Y., Zhu, Y., Xie, S. Z. & Qin, L. X. Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives. J. Hematol. Oncol. 17, 25 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jing, Y. et al. Remodelling hypoxic TNBC microenvironment restores antitumor efficacy of Vγ9Vδ2 T cell therapy. Br. J. Cancer 133, 365–380 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hayati, M. J. et al. Gamma delta T cells in the tumour microenvironment: a double-edged sword. Immunology 177, 44–58 (2026).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lanng, K. R. B., Lauridsen, E. L. & Jakobsen, M. R. The balance of STING signaling orchestrates immunity in cancer. Nat. Immunol. 25, 1144–1157 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Richter, F., Paget, C. & Apetoh, L. STING-driven activation of T cells: relevance for the adoptive cell therapy of cancer. Cell Stress 7, 95–104 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Serrano, R. et al. Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells. Oncoimmunology 11, 2030021 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luo, J. et al. γδ T cell-mediated tumor immunity is tightly regulated by STING and TGF-β signaling pathways. Adv. Sci. 12, e2404432 (2025).

    Article 

    Google Scholar
     

  • Scirgolea, C. et al. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy. Nat. Immunol. 25, 1845–1857 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Soll, D. et al. Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity. Nat. Immunol. 25, 1830–1844 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Parthasarathy, A., Li, T. & Edelblum, K. L. Crosstalk between the microbiota and intestinal γδ T cell compartments in health and IBD. Gut Microbes 18, 2604908 (2026).

    Article 
    PubMed 

    Google Scholar
     

  • Dai, Y., Chen, H., Mo, C., Cui, L. & He, W. Ectopically expressed human tumor biomarker MutS homologue 2 is a novel endogenous ligand that is recognized by human γδ T cells to induce innate anti-tumor/virus immunity. J. Biol. Chem. 287, 16812–16819 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luoma, A. M. et al. Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells. Immunity 39, 1032–1042 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Uldrich, A. P. et al. CD1d-lipid antigen recognition by the γδ TCR. Nat. Immunol. 14, 1137–1145 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu, B. et al. Crystal structure of a γδ T-cell receptor specific for the human MHC class I homolog MICA. Proc. Natl Acad. Sci. USA 108, 2414–2419 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • You, H. et al. γδ T-cell autoresponses to ectopic membrane proteins: a new type of pattern recognition. Cell. Mol. Immunol. 22, 356–370 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harly, C. et al. Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2. Sci. Immunol. 6, eaba9010 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Marlin, R. et al. Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2. Proc. Natl Acad. Sci. USA 114, 3163–3168 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Willcox, C. R. et al. Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. Nat. Immunol. 13, 872–879 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar