Exploration of Immunology

Feature	Vδ1	Vδ2	Vδ3, non-Vδ1- Vδ2	Context dependency
Friends	Cytotoxic, NKp46⁺	Cytotoxic, IFN-γ, TNF-α, pAg, ADCC		MSI, high immune infiltration IL-15
Foes	IL-17, AREG, TGF-β, Galectin 3 LAIR-1, other inhibitory receptors	LAIR-1, other inhibitory receptors	IL-17, AREG, TGF-β, Galectin 3	Stromal-rich CRC (CMS4) Low infiltration IL-1β

Declarations

Acknowledgments

All the figures have been designed from the templates of Anatomy and Human Body and Cellular Biology series of Smart Servier Medical Art (https://smart.servier.com/).

Author contributions

AP: Conceptualization, Investigation, Validation, Supervision, Writing—original draft, Writing—review & editing. The author read and approved the submitted version.

Conflicts of interest

The author declares that he has no conflicts of interest.

Ethical approval

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Availability of data and materials

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Funding

The manuscript has been supported by the grant AIRCIG21648 to AP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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References

Saito H, Kranz DM, Takagaki Y, Hayday AC, Eisen HN, Tonegawa S. Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. Nature. 1984;309:757–62. [DOI] [PubMed]

Hayday AC, Saito H, Gillies SD, Kranz DM, Tanigawa G, Eisen HN, et al. Structure, organization, and somatic rearrangement of T cell gamma genes. Cell. 1985;40:259–69. [DOI] [PubMed]

Lefranc MP, Rabbitts TH. Two tandemly organized human genes encoding the T-cell gamma constant-region sequences show multiple rearrangement in different T-cell types. Nature. 1985;316:464–6. [DOI] [PubMed]

Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA, Owen FL, et al. Identification of a putative second T-cell receptor. Nature. 1986;322:145–9. [DOI] [PubMed]

Li GQ, Xia J, Zeng W, Luo W, Liu L, Zeng X, et al. The intestinal γδ T cells: functions in the gut and in the distant organs. Front Immunol. 2023;14:1206299. [DOI] [PubMed] [PMC]

Mohamed AA, Al-Ramadi BK, Fernandez-Cabezudo MJ. Interplay between Microbiota and γδ T Cells: Insights into Immune Homeostasis and Neuro-Immune Interactions. Int J Mol Sci. 2024;25:1747. [DOI] [PubMed] [PMC]

Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X, Benjamin JL, et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A. 2011;108:8743–8. [DOI] [PubMed] [PMC]

Chien YH, Meyer C, Bonneville M. γδ T cells: first line of defense and beyond. Annu Rev Immunol. 2014;32:121–55. [DOI] [PubMed]

Bakker AB, Phillips JH, Figdor CG, Lanier LL. Killer cell inhibitory receptors for MHC class I molecules regulate lysis of melanoma cells mediated by NK cells, gamma delta T cells, and antigen-specific CTL. J Immunol. 1998;160:5239–45. [PubMed]

10.

Mingari MC, Vitale C, Cambiaggi A, Schiavetti F, Melioli G, Ferrini S, et al. Cytolytic T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production. Int Immunol. 1995;7:697–703. [DOI] [PubMed]

11.

Karjalainen H, Härkönen J, Sirniö P, Elomaa H, Äijälä VK, Kastinen M, et al. Characteristics and significance of γδ T cells in colorectal cancer. Oncoimmunology. 2025;14:2532231. [DOI] [PubMed] [PMC]

12.

Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A. 2002;99:14338–43. [DOI] [PubMed] [PMC]

13.

Ismail AS, Behrendt CL, Hooper LV. Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J Immunol. 2009;182:3047–54. [DOI] [PubMed] [PMC]

14.

Edelblum KL, Singh G, Odenwald MA, Lingaraju A, El Bissati K, McLeod R, et al. γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. Gastroenterology. 2015;148:1417–26. [DOI] [PubMed] [PMC]

15.

Rampoldi F, Prinz I. Three Layers of Intestinal γδ T Cells Talk Different Languages With the Microbiota. Front Immunol. 2022;13:849954. [DOI] [PubMed] [PMC]

16.

Hu MD, Ethridge AD, Lipstein R, Kumar S, Wang Y, Jabri B, et al. Epithelial IL-15 Is a Critical Regulator of γδ Intraepithelial Lymphocyte Motility within the Intestinal Mucosa. J Immunol. 2018;201:747–56. [DOI] [PubMed] [PMC]

17.

Martínez-Vargas IU, Sánchez-Bello ME, Miguel-Rodríguez CE, Hernández-Cázares F, Santos-Argumedo L, Talamás-Rohana P. Myo1f has an essential role in γδT intraepithelial lymphocyte adhesion and migration. Front Immunol. 2023;14:1041079. [DOI] [PubMed] [PMC]

18.

Bonneville M, Janeway CA Jr, Ito K, Haser W, Ishida I, Nakanishi N, et al. Intestinal intraepithelial lymphocytes are a distinct set of gamma delta T cells. Nature. 1988;336:479–81. [DOI] [PubMed]

19.

Goodman T, Lefrançois L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature. 1988;333:855–8. [DOI] [PubMed]

20.

Lin T, Matsuzaki G, Umesue M, Omoto K, Yoshida H, Harada M, et al. Development of TCR-gamma delta CD4-CD8+ alpha alpha but not TCR-alpha beta CD4-CD8+ alpha alpha i-IEL is resistant to cyclosporin A. J Immunol. 1995;155:4224–30. [PubMed]

21.

Takagaki Y, DeCloux A, Bonneville M, Tonegawa S. Diversity of gamma delta T-cell receptors on murine intestinal intra-epithelial lymphocytes. Nature. 1989;339:712–4. [DOI] [PubMed]

22.

Di Marco Barros R, Roberts NA, Dart RJ, Vantourout P, Jandke A, Nussbaumer O, et al. Epithelia Use Butyrophilin-like Molecules to Shape Organ-Specific γδ T Cell Compartments. Cell. 2016;167:203–18.e17. [DOI] [PubMed] [PMC]

23.

Kenna T, Golden-Mason L, Norris S, Hegarty JE, O’Farrelly C, Doherty DG. Distinct subpopulations of gamma delta T cells are present in normal and tumor-bearing human liver. Clin Immunol. 2004;113:56–63. [DOI] [PubMed]

24.

El-Asady R, Yuan R, Liu K, Wang D, Gress RE, Lucas PJ, et al. TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. J Exp Med. 2005;201:1647–57. [DOI] [PubMed] [PMC]

25.

Grueter B, Petter M, Egawa T, Laule-Kilian K, Aldrian CJ, Wuerch A, et al. Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells. J Immunol. 2005;175:1694–705. [DOI] [PubMed]

26.

Ericsson A, Svensson M, Arya A, Agace WW. CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes. Eur J Immunol. 2004;34:2720–9. [DOI] [PubMed]

27.

Chennupati V, Worbs T, Liu X, Malinarich FH, Schmitz S, Haas JD, et al. Intra- and intercompartmental movement of gammadelta T cells: intestinal intraepithelial and peripheral gammadelta T cells represent exclusive nonoverlapping populations with distinct migration characteristics. J Immunol. 2010;185:5160–8. [DOI] [PubMed]

28.

Uehara S, Grinberg A, Farber JM, Love PE. A role for CCR9 in T lymphocyte development and migration. J Immunol. 2002;168:2811–9. [DOI] [PubMed]

29.

Wurbel MA, Malissen M, Guy-Grand D, Meffre E, Nussenzweig MC, Richelme M, et al. Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood. 2001;98:2626–32. [DOI] [PubMed]

30.

Kabelitz D, Wesch D. Features and functions of gamma delta T lymphocytes: focus on chemokines and their receptors. Crit Rev Immunol. 2003;23:339–70. [DOI] [PubMed]

31.

Wagner N, Löhler J, Kunkel EJ, Ley K, Leung E, Krissansen G, et al. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature. 1996;382:366–70. [DOI] [PubMed]

32.

Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and regional immunity. Adv Immunol. 1999;72:209–53. [DOI] [PubMed]

33.

Xu W, Bergsbaken T, Edelblum KL. The multifunctional nature of CD103 (αEβ7 integrin) signaling in tissue-resident lymphocytes. Am J Physiol Cell Physiol. 2022;323:C1161–7. [DOI] [PubMed] [PMC]

34.

Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21:527–38. [DOI] [PubMed]

35.

Gyöngyösi A, Szatmari I, Pap A, Dezso B, Pos Z, Széles L, et al. RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells. J Lipid Res. 2013;54:2458–74. [DOI] [PubMed] [PMC]

36.

Li J, Xiao C, Li C, He J. Tissue-resident immune cells: from defining characteristics to roles in diseases. Signal Transduct Target Ther. 2025;10:12. [DOI] [PubMed] [PMC]

37.

Oida T, Suzuki K, Nanno M, Kanamori Y, Saito H, Kubota E, et al. Role of gut cryptopatches in early extrathymic maturation of intestinal intraepithelial T cells. J Immunol. 2000;164:3616–26. [DOI] [PubMed]

38.

Porter BO, Malek TR. Thymic and intestinal intraepithelial T lymphocyte development are each regulated by the gammac-dependent cytokines IL-2, IL-7, and IL-15. Semin Immunol. 2000;12:465–74. [DOI] [PubMed]

39.

Gray JI, Farber DL. Tissue-Resident Immune Cells in Humans. Annu Rev Immunol. 2022;40:195–220. [DOI] [PubMed] [PMC]

40.

Fischer MA, Golovchenko NB, Edelblum KL. γδ T cell migration: Separating trafficking from surveillance behaviors at barrier surfaces. Immunol Rev. 2020;298:165–80. [DOI] [PubMed] [PMC]

41.

Hu Y, Hu Q, Li Y, Lu L, Xiang Z, Yin Z, et al. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther. 2023;8:434. [DOI] [PubMed] [PMC]

42.

Yang H, Spencer AU, Teitelbaum DH. Interleukin-7 administration alters intestinal intraepithelial lymphocyte phenotype and function in vivo. Cytokine. 2005;31:419–28. [DOI] [PubMed]

43.

Wang X, Sumida H, Cyster JG. GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment. J Exp Med. 2014;211:2351–9. [DOI] [PubMed] [PMC]

44.

Sumida H, Lu E, Chen H, Yang Q, Mackie K, Cyster JG. GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage. Sci Immunol. 2017;2:eaao1135. [DOI] [PubMed] [PMC]

45.

Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011;147:629–40. [DOI] [PubMed]

46.

Xu B, Ji J, Ma L, Wang C, Pang L, Song Q, et al. γδT Cells in IBD: Beneficial or Detrimental? Immunology. 2025;176:337–48. [DOI] [PubMed]

47.

Parthasarathy A, Li T, Edelblum KL. Crosstalk between the microbiota and intestinal γδ T cell compartments in health and IBD. Gut Microbes. 2026;18:2604908. [DOI] [PubMed] [PMC]

48.

Ran R, Brubaker DK. A ligand-centered framework for γδ T cell activation in colorectal cancer revealed by single-cell and transformer-based perturbation. Front Immunol. 2026;16:1715827. [DOI] [PubMed] [PMC]

49.

Ran R, Trapecar M, Brubaker DK. Systematic analysis of human colorectal cancer scRNA-seq revealed limited pro-tumoral IL-17 production potential in gamma delta T cells. Neoplasia. 2024;58:101072. [DOI] [PubMed] [PMC]

50.

Corsale AM, Di Simone M, Lo Presti E, Dieli F, Meraviglia S. γδ T cells and their clinical application in colon cancer. Front Immunol. 2023;14:1098847. [DOI] [PubMed] [PMC]

51.

Rodin W, Szeponik L, Rangelova T, Tamiru Kebede F, Österlund T, Sundström P, et al. γδ T cells in human colon adenocarcinomas comprise mainly Vδ1, Vδ2, and Vδ3 cells with distinct phenotype and function. Cancer Immunol Immunother. 2024;73:174. [DOI] [PubMed] [PMC]

52.

Andreu-Ballester JC, Cuéllar C, Colmena-Zaragoza J, Galindo-Regal L, Hurtado-Marcos C, González-Fernández J, et al. Anti-Anisakis antibodies in colon cancer patients and their relationship with γδ T-cells. Parasitol Res. 2024;123:196. [DOI] [PubMed] [PMC]

53.

Pan L, Zhou Y, Kuang Y, Wang C, Wang W, Hu X, et al. Progress of research on γδ T cells in colorectal cancer (Review). Oncol Rep. 2024;52:160. [DOI] [PubMed] [PMC]

54.

Reis BS, Darcy PW, Khan IZ, Moon CS, Kornberg AE, Schneider VS, et al. TCR-Vγδ usage distinguishes protumor from antitumor intestinal γδ T cell subsets. Science. 2022;377:276–84. [DOI] [PubMed] [PMC]

55.

Zhao Y, Niu C, Cui J. Gamma-delta (γδ) T cells: friend or foe in cancer development? J Transl Med. 2018;16:3. [DOI] [PubMed] [PMC]

56.

Li Y, Li G, Zhang J, Wu X, Chen X. The Dual Roles of Human γδ T Cells: Anti-Tumor or Tumor-Promoting. Front Immunol. 2021;11:619954. [DOI] [PubMed] [PMC]

57.

Saran A, Nishizaki D, Lippman SM, Kato S, Kurzrock R. Interleukin-17: A pleiotropic cytokine implicated in inflammatory, infectious, and malignant disorders. Cytokine Growth Factor Rev. 2025;83:35–44. [DOI] [PubMed]

58.

Wu P, Wu D, Ni C, Ye J, Chen W, Hu G, et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity. 2014;40:785–800. [DOI] [PubMed] [PMC]

59.

Ferrarini M, Ferrero E, Dagna L, Poggi A, Zocchi MR. Human gammadelta T cells: a nonredundant system in the immune-surveillance against cancer. Trends Immunol. 2002;23:14–8. [DOI] [PubMed]

60.

Masetti R, Tiri A, Tignanelli A, Turrini E, Argentiero A, Pession A, et al. Autoimmunity and cancer. Autoimmun Rev. 2021;20:102882. [DOI] [PubMed]

61.

Poggi A, Zocchi MR. Human natural killer lymphocytes through the engagement of natural cytotoxicity receptors and NKG2D can trigger self-aggression. Autoimmun Rev. 2007;6:295–9. [DOI] [PubMed]

62.

Burke KP, Grebinoski S, Sharpe AH, Vignali DAA. Understanding adverse events of immunotherapy: A mechanistic perspective. J Exp Med. 2021;218:e20192179. [DOI] [PubMed] [PMC]

63.

Chamoto K, Yaguchi T, Tajima M, Honjo T. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1. Nat Rev Immunol. 2023;23:682–95. [DOI] [PubMed]

64.

Fujiwara Y, Kato S, Nesline MK, Conroy JM, DePietro P, Pabla S, et al. Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy. Cancer Treat Rev. 2022;110:102461. [DOI] [PubMed] [PMC]

65.

Sieminska I, Baran J. Myeloid-Derived Suppressor Cells in Colorectal Cancer. Front Immunol. 2020;11:1526. [DOI] [PubMed] [PMC]

66.

Mellor AL, Lemos H, Huang L. Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now? Front Immunol. 2017;8:1360. [DOI] [PubMed] [PMC]

67.

Ishihara S, Yamada Y, Iwasaki T, Yoshimoto M, Toda Y, Kohashi K, et al. PD-L1 and IDO-1 expression in undifferentiated pleomorphic sarcoma: The associations with tumor infiltrating lymphocytes, dMMR and HLA class I. Oncol Rep. 2021;45:379–89. [DOI] [PubMed]

68.

Leonard NA, Corry SM, Reidy E, Egan H, O’Malley G, Thompson K, et al. Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling. iScience. 2024;27:110701. [DOI] [PubMed] [PMC]

69.

Chen YL, Wang GX, Lin BA, Huang JS. MicroRNA-93-5p expression in tumor tissue and its tumor suppressor function via targeting programmed death ligand-1 in colorectal cancer. Cell Biol Int. 2020;44:1224–36. [DOI] [PubMed]

70.

Lin KX, Istl AC, Quan D, Skaro A, Tang E, Zheng X. PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies. Cancer Immunol Immunother. 2023;72:3875–93. [DOI] [PubMed] [PMC]

71.

Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity. 2007;27:334–48. [DOI] [PubMed]

72.

Harmon C, Zaborowski A, Moore H, St Louis P, Slattery K, Duquette D, et al. γδ T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors. Nat Cancer. 2023;4:1122–37. [DOI] [PubMed]

73.

Szeponik L, Akeus P, Rodin W, Raghavan S, Quiding-Järbrink M. Regulatory T cells specifically suppress conventional CD8αβ T cells in intestinal tumors of APC^Min/+ mice. Cancer Immunol Immunother. 2020;69:1279–92. [DOI] [PubMed] [PMC]

74.

Amicarella F, Muraro MG, Hirt C, Cremonesi E, Padovan E, Mele V, et al. Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut. 2017;66:692–704. [DOI] [PubMed] [PMC]

75.

Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–7. [DOI] [PubMed]

76.

Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15:1016–22. [DOI] [PubMed] [PMC]

77.

Mikulak J, Oriolo F, Bruni E, Roberto A, Colombo FS, Villa A, et al. NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI Insight. 2019;4:e125884. [DOI] [PubMed] [PMC]

78.

Tosolini M, Pont F, Poupot M, Vergez F, Nicolau-Travers ML, Vermijlen D, et al. Assessment of tumor-infiltrating TCRVγ9Vδ2 γδ lymphocyte abundance by deconvolution of human cancers microarrays. Oncoimmunology. 2017;6:e1284723. [DOI] [PubMed] [PMC]

79.

Meraviglia S, Lo Presti E, Tosolini M, La Mendola C, Orlando V, Todaro M, et al. Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer. Oncoimmunology. 2017;6:e1347742. [DOI] [PubMed] [PMC]

80.

Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8. [DOI] [PubMed]

81.

Bejarano L, Jordāo MJC, Joyce JA. Therapeutic Targeting of the Tumor Microenvironment. Cancer Discov. 2021;11:933–59. [DOI] [PubMed]

82.

Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41:421–33. [DOI] [PubMed] [PMC]

83.

Al Zein M, Boukhdoud M, Shammaa H, Mouslem H, El Ayoubi LM, Iratni R, et al. Immunotherapy and immunoevasion of colorectal cancer. Drug Discov Today. 2023;28:103669. [DOI] [PubMed]

84.

Ganapathy T, Radhakrishnan R, Sakshi S, Martin S. CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green? Cancer Immunol Immunother. 2023;72:277–86. [DOI] [PubMed] [PMC]

85.

Saura-Esteller J, de Jong M, King LA, Ensing E, Winograd B, de Gruijl TD, et al. Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future. Front Immunol. 2022;13:915837. [DOI] [PubMed] [PMC]

86.

Uhrberg M, Valiante NM, Young NT, Lanier LL, Phillips JH, Parham P. The repertoire of killer cell Ig-like receptor and CD94:NKG2A receptors in T cells: clones sharing identical alpha beta TCR rearrangement express highly diverse killer cell Ig-like receptor patterns. J Immunol. 2001;166:3923–32. [DOI] [PubMed]

87.

Barakonyi A, Kovacs KT, Miko E, Szereday L, Varga P, Szekeres-Bartho J. Recognition of nonclassical HLA class I antigens by gamma delta T cells during pregnancy. J Immunol. 2002;168:2683–8. [DOI] [PubMed]

88.

Dolstra H, Fredrix H, van der Meer A, de Witte T, Figdor C, van de Wiel-van Kemenade E. TCR gamma delta cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells. Bone Marrow Transplant. 2001;27:1087–93. [DOI] [PubMed]

89.

Poccia F, Cipriani B, Vendetti S, Colizzi V, Poquet Y, Battistini L, et al. CD94/NKG2 inhibitory receptor complex modulates both anti-viral and anti-tumoral responses of polyclonal phosphoantigen-reactive V gamma 9V delta 2 T lymphocytes. J Immunol. 1997;159:6009–17. [PubMed]

90.

Rong L, Li K, Li R, Liu HM, Sun R, Liu XY. Analysis of tumor-infiltrating gamma delta T cells in rectal cancer. World J Gastroenterol. 2016;22:3573–80. [DOI] [PubMed] [PMC]

91.

Halary F, Peyrat MA, Champagne E, Lopez-Botet M, Moretta A, Moretta L, et al. Control of self-reactive cytotoxic T lymphocytes expressing gamma delta T cell receptors by natural killer inhibitory receptors. Eur J Immunol. 1997;27:2812–21. [DOI] [PubMed]

92.

Takamizawa M, Fagnoni F, Mehta-Damani A, Rivas A, Engleman EG. Cellular and molecular basis of human gamma delta T cell activation. Role of accessory molecules in alloactivation. J Clin Invest. 1995;95:296–303. [DOI] [PubMed] [PMC]

93.

Poggi A, Contini P, Catellani S, Setti M, Murdaca G, Zocchi MR. Regulation of gammadelta T cell survival by soluble HLA-I: involvement of CD8 and activating killer Ig-like receptors. Eur J Immunol. 2005;35:2670–8. [DOI] [PubMed]

94.

Kondo M, Izumi T, Fujieda N, Kondo A, Morishita T, Matsushita H, et al. Expansion of human peripheral blood γδ T cells using zoledronate. J Vis Exp. 2011:3182. [DOI] [PubMed] [PMC]

95.

Musso A, Catellani S, Canevali P, Tavella S, Venè R, Boero S, et al. Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vδ 2 T lymphocytes in non-Hodgkin lymphomas. Haematologica. 2014;99:131–9. [DOI] [PubMed] [PMC]

96.

Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015;33:169–200. [DOI] [PubMed]

97.

Loureiro JP, Vacchini A, Berloffa G, Devan J, Schaefer V, Nosi V, et al. Recognition of MR1-antigen complexes by TCR Vγ9Vδ2. Front Immunol. 2025;16:1519128. [DOI] [PubMed] [PMC]

98.

Eberl M, Mata Forsberg M, McLaren JE, Sverremark-Ekström E. Microbe-responsive human γδ T cells: the peculiar case of Staphylococcus aureus. Immunol Cell Biol. 2025;103:938–44. [DOI] [PubMed] [PMC]

99.

Tuffs SW, Dufresne K, Rishi A, Walton NR, McCormick JK. Novel insights into the immune response to bacterial T cell superantigens. Nat Rev Immunol. 2024;24:417–34. [DOI] [PubMed]

100.

Mocchegiani E, Giacconi R, Cipriano C, Gasparini N, Bernardini G, Malavolta M, et al. The variations during the circadian cycle of liver CD1d-unrestricted NK1.1+TCR gamma/delta+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice. Exp Gerontol. 2004;39:775–88. [DOI] [PubMed]

101.

Xi C, Jia Z, Xiaoli W, Na Z, He W, Hao J. New Aspect of Liver IL-17⁺γδ T Cells. Mol Immunol. 2019;107:41–3. [DOI] [PubMed]

102.

Jameson J, Witherden D, Havran WL. T-cell effector mechanisms: gammadelta and CD1d-restricted subsets. Curr Opin Immunol. 2003;15:349–53. [DOI] [PubMed]

103.

Kaufmann SH, Kabelitz D. Gamma/delta T lymphocytes and heat shock proteins. Curr Top Microbiol Immunol. 1991;167:191–207. [DOI] [PubMed]

104.

Mohammed SS, Alkhalifah AKS, Mirza R, Okinedo SO, Inampudi RA, Bibi A, et al. Follicular helper-like γδ T cells promote plasma cell differentiation in Behçet’s disease. Front Immunol. 2026;17:1763174. [DOI] [PubMed] [PMC]

105.

Wang S, Li H, Chen T, Zhou H, Zhang W, Lin N, et al. Human γδ T cells induce CD8⁺ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK. Cancer Immunol Immunother. 2023;72:1803–21. [DOI] [PubMed] [PMC]

106.

Eberl M, Hintz M, Reichenberg A, Kollas AK, Wiesner J, Jomaa H. Microbial isoprenoid biosynthesis and human gammadelta T cell activation. FEBS Lett. 2003;544:4–10. [DOI] [PubMed]

107.

Eberl M, Engel R, Aberle S, Fisch P, Jomaa H, Pircher H. Human Vgamma9/Vdelta2 effector memory T cells express the killer cell lectin-like receptor G1 (KLRG1). J Leukoc Biol. 2005;77:67–70. [DOI] [PubMed]

108.

Iwasaki M, Tanaka Y, Kobayashi H, Murata-Hirai K, Miyabe H, Sugie T, et al. Expression and function of PD-1 in human γδ T cells that recognize phosphoantigens. Eur J Immunol. 2011;41:345–55. [DOI] [PubMed]

109.

Lafont V, Liautard J, Sable-Teychene M, Sainte-Marie Y, Favero J. Isopentenyl pyrophosphate, a mycobacterial non-peptidic antigen, triggers delayed and highly sustained signaling in human gamma delta T lymphocytes without inducing eown-modulation of T cell antigen receptor. J Biol Chem. 2001;276:15961–7. [DOI] [PubMed]

110.

Jauhiainen M, Mönkkönen H, Räikkönen J, Mönkkönen J, Auriola S. Analysis of endogenous ATP analogs and mevalonate pathway metabolites in cancer cell cultures using liquid chromatography-electrospray ionization mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:2967–75. [DOI] [PubMed]

111.

Couzi L, Pitard V, Moreau JF, Merville P, Déchanet-Merville J. Direct and Indirect Effects of Cytomegalovirus-Induced γδ T Cells after Kidney Transplantation. Front Immunol. 2015;6:3. [DOI] [PubMed] [PMC]

112.

Willcox CR, Vantourout P, Salim M, Zlatareva I, Melandri D, Zanardo L, et al. Butyrophilin-like 3 Directly Binds a Human Vγ4⁺ T Cell Receptor Using a Modality Distinct from Clonally-Restricted Antigen. Immunity. 2019;51:813–25.e4. [DOI] [PubMed] [PMC]

113.

Harly C, Joyce SP, Domblides C, Bachelet T, Pitard V, Mannat C, et al. Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2. Sci Immunol. 2021;6:eaba9010. [DOI] [PubMed]

114.

You H, Zhang X, Chen H, Liu C, Teng D, Han J, et al. γδ T-cell autoresponses to ectopic membrane proteins: a new type of pattern recognition. Cell Mol Immunol. 2025;22:356–70. [DOI] [PubMed] [PMC]

115.

Van Rhijn I, Le Nours J. CD1 and MR1 recognition by human γδ T cells. Mol Immunol. 2021;133:95–100. [DOI] [PubMed] [PMC]

116.

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. 2012;287:16812–9. [DOI] [PubMed] [PMC]

117.

Sakuraba S, Koizumi A, Iwasawa T, Ito T, Kato K. Serum EphA2 as a Promising Biomarker for the Early Detection and Diagnosis of Colorectal Cancer. Biomolecules. 2024;14:1504. [DOI] [PubMed] [PMC]

118.

Roelofs AJ, Jauhiainen M, Mönkkönen H, Rogers MJ, Mönkkönen J, Thompson K. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol. 2009;144:245–50. [DOI] [PubMed] [PMC]

119.

Okuno D, Sugiura Y, Sakamoto N, Tagod MSO, Iwasaki M, Noda S, et al. Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells. Front Immunol. 2020;11:1405. [DOI] [PubMed] [PMC]

120.

Fernandez JLC, Benelli R, Costa D, Campioli A, Tavella S, Zocchi MR, et al. Priming of Colorectal Tumor-Associated Fibroblasts with Zoledronic Acid Conjugated to the Anti-Epidermal Growth Factor Receptor Antibody Cetuximab Elicits Anti-Tumor Vδ2 T Lymphocytes. Cancers (Basel). 2023;15:610. [DOI] [PubMed] [PMC]

121.

Lv J, Liu Z, Ren X, Song S, Zhang Y, Wang Y. γδT cells, a key subset of T cell for cancer immunotherapy. Front Immunol. 2025;16:1562188. [DOI] [PubMed] [PMC]

122.

Serrano R, Wesch D, Kabelitz D. Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes. Cells. 2020;9:713. [DOI] [PubMed] [PMC]

123.

Vavassori S, Kumar A, Wan GS, Ramanjaneyulu GS, Cavallari M, El Daker S, et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat Immunol. 2013;14:908–16. [DOI] [PubMed]

124.

Rigau M, Ostrouska S, Fulford TS, Johnson DN, Woods K, Ruan Z, et al. Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science. 2020;367:eaay5516. [DOI] [PubMed]

125.

Vantourout P, Laing A, Woodward MJ, Zlatareva I, Apolonia L, Jones AW, et al. Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology. Proc Natl Acad Sci U S A. 2018;115:1039–44. [DOI] [PubMed] [PMC]

126.

Fulford TS, Soliman C, Castle RG, Rigau M, Ruan Z, Dolezal O, et al. Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers. Nat Immunol. 2024;25:1355–66. [DOI] [PubMed]

127.

Cano CE, Pasero C, De Gassart A, Kerneur C, Gabriac M, Fullana M, et al. BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells. Cell Rep. 2021;36:109359. [DOI] [PubMed]

128.

Karunakaran MM, Subramanian H, Jin Y, Mohammed F, Kimmel B, Juraske C, 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. 2023;14:7617. [DOI] [PubMed] [PMC]

129.

Benelli R, Costa D, Salvini L, Tardito S, Tosetti F, Villa F, et al. Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab. J Immunother Cancer. 2022;10:e005660. [DOI] [PubMed] [PMC]

130.

Cipriani B, Knowles H, Chen L, Battistini L, Brosnan CF. Involvement of classical and novel protein kinase C isoforms in the response of human V gamma 9V delta 2 T cells to phosphate antigens. J Immunol. 2002;169:5761–70. [DOI] [PubMed]

131.

Idrees AS, Sugie T, Inoue C, Murata-Hirai K, Okamura H, Morita CT, et al. Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid. Cancer Sci. 2013;104:536–42. [DOI] [PubMed] [PMC]

132.

Wang H, Sarikonda G, Puan KJ, Tanaka Y, Feng J, Giner JL, et al. Indirect stimulation of human Vγ2Vδ2 T cells through alterations in isoprenoid metabolism. J Immunol. 2011;187:5099–113. [DOI] [PubMed] [PMC]

133.

Das H, Wang L, Kamath A, Bukowski JF. Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates. Blood. 2001;98:1616–8. [DOI] [PubMed]

134.

Pisheh L, Matis S, Taglieri M, Di Gregorio L, Benelli R, Poggi A. EGFR-Targeted Antibody-Drug Conjugate to Different Aminobisphosphonates: Direct and Indirect Antitumor Effects on Colorectal Carcinoma Cells. Cancers (Basel). 2024;16:1256. [DOI] [PubMed] [PMC]

135.

Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT, et al. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011;49:20–33. [DOI] [PubMed]

136.

Ohno K, Mori K, Orita M, Takeuchi M. Computational insights into binding of bisphosphates to farnesyl pyrophosphate synthase. Curr Med Chem. 2011;18:220–33. [DOI] [PubMed] [PMC]

137.

Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008;19:733–59. [DOI] [PubMed]

138.

Ferry GM, Agbuduwe C, Forrester M, Dunlop S, Chester K, Fisher J, et al. A Simple and Robust Single-Step Method for CAR-Vδ1 γδT Cell Expansion and Transduction for Cancer Immunotherapy. Front Immunol. 2022;13:863155. [DOI] [PubMed] [PMC]

139.

Vyborova A, Gasull-Celades L, Brazda P, Bedate AM, Karaiskaki F, Sanders J, et al. Pre-existing activation states shape functional heterogeneity of human Vγ9Vδ2 T cells. Front Immunol. 2026;17:1696469. [DOI] [PubMed] [PMC]

140.

Bruni E, Cazzetta V, Donadon M, Cimino M, Torzilli G, Spata G, et al. Chemotherapy accelerates immune-senescence and functional impairments of Vδ2^pos T cells in elderly patients affected by liver metastatic colorectal cancer. J Immunother Cancer. 2019;7:347. [DOI] [PubMed] [PMC]

141.

Caccamo N, Meraviglia S, Ferlazzo V, Angelini D, Borsellino G, Poccia F, et al. Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vgamma9Vdelta2 naive, memory and effector T cell subsets. Eur J Immunol. 2005;35:1764–72. [DOI] [PubMed]

142.

Deniger DC, Maiti SN, Mi T, Switzer KC, Ramachandran V, Hurton LV, et al. Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies. Clin Cancer Res. 2014;20:5708–19. [DOI] [PubMed] [PMC]

143.

Knight A, Mackinnon S, Lowdell MW. Human Vdelta1 gamma-delta T cells exert potent specific cytotoxicity against primary multiple myeloma cells. Cytotherapy. 2012;14:1110–8. [DOI] [PubMed]

144.

Niu C, Jin H, Li M, Zhu S, Zhou L, Jin F, et al. Low-dose bortezomib increases the expression of NKG2D and DNAM-1 ligands and enhances induced NK and γδ T cell-mediated lysis in multiple myeloma. Oncotarget. 2017;8:5954–64. [DOI] [PubMed] [PMC]

145.

Poggi A, Zancolli M, Boero S, Catellani S, Musso A, Zocchi MR. Differential survival of γδT cells, αβT cells and NK cells upon engagement of NKG2D by NKG2DL-expressing leukemic cells. Int J Cancer. 2011;129:387–96. [DOI] [PubMed]

146.

Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999;285:727–9. [DOI] [PubMed]

147.

Kyrysyuk O, Wucherpfennig KW. Designing Cancer Immunotherapies That Engage T Cells and NK Cells. Annu Rev Immunol. 2023;41:17–38. [DOI] [PubMed] [PMC]

148.

Zocchi MR, Catellani S, Canevali P, Tavella S, Garuti A, Villaggio B, et al. High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood. 2012;119:1479–89. [DOI] [PubMed]

149.

Shibuya K, Lanier LL, Phillips JH, Ochs HD, Shimizu K, Nakayama E, et al. Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity. 1999;11:615–23. [DOI] [PubMed]

150.

Tahara-Hanaoka S, Shibuya K, Onoda Y, Zhang H, Yamazaki S, Miyamoto A, et al. Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112). Int Immunol. 2004;16:533–8. [DOI] [PubMed]

151.

Drewniak-Świtalska M, Fortuna P, Krzystek-Korpacka M. Negative Immune Checkpoint Inhibitors. Pharmaceutics. 2025;17:713. [DOI] [PubMed] [PMC]

152.

Roussot N, Kaderbhai C, Ghiringhelli F. Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1/PD-L1 Monoclonal Antibodies. Cancers (Basel). 2025;17:906. [DOI] [PubMed] [PMC]

153.

Zamani P, Barootchi E, Firouzabadi A, Tonekaboni MS, Saleki K, Yazdanpanah N, et al. Targeting T cell exhaustion in colorectal cancer: emerging roles of LAG-3, TIM-3, and TIGIT signaling in overcoming immunotherapy resistance. Cell Commun Signal. 2026;24:81. [DOI] [PubMed] [PMC]

154.

Poggi A, Zocchi MR. Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges. Mol Ther Oncolytics. 2021;24:26–42. [DOI] [PubMed] [PMC]

155.

Zumwalde NA, Sharma A, Xu X, Ma S, Schneider CL, Romero-Masters JC, et al. Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model. JCI Insight. 2017;2:e93179. [DOI] [PubMed] [PMC]

156.

Nada MH, Wang H, Hussein AJ, Tanaka Y, Morita CT. PD-1 checkpoint blockade enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against human prostate cancer. Oncoimmunology. 2021;10:1989789. [DOI] [PubMed] [PMC]

157.

Fenn J, Ridgley LA, White A, Sarfas C, Dennis M, Dalgleish A, et al. Bacillus Calmette-Guerin (BCG) induces superior anti-tumour responses by Vδ2+ T cells compared with the aminobisphosphonate drug zoledronic acid. Clin Exp Immunol. 2022;208:301–15. [DOI] [PubMed] [PMC]

158.

Varesano S, Zocchi MR, Poggi A. Zoledronate Triggers Vδ2 T Cells to Destroy and Kill Spheroids of Colon Carcinoma: Quantitative Image Analysis of Three-Dimensional Cultures. Front Immunol. 2018;9:998. [DOI] [PubMed] [PMC]

159.

Hoeres T, Smetak M, Pretscher D, Wilhelm M. Improving the Efficiency of Vγ9Vδ2 T-Cell Immunotherapy in Cancer. Front Immunol. 2018;9:800. [DOI] [PubMed] [PMC]

160.

Xu Y, Xiang Z, Alnaggar M, Kouakanou L, Li J, He J, 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. 2021;18:427–39. [DOI] [PubMed] [PMC]

161.

Wu D, Wu P, Wu X, Ye J, Wang Z, Zhao S, et al. Ex vivo expanded human circulating Vδ1 γδT cells exhibit favorable therapeutic potential for colon cancer. Oncoimmunology. 2015;4:e992749. [DOI] [PubMed] [PMC]

162.

Rancan C, Arias-Badia M, Dogra P, Chen B, Aran D, Yang H, et al. Exhausted intratumoral Vδ2^- γδ T cells in human kidney cancer retain effector function. Nat Immunol. 2023;24:612–24. [DOI] [PubMed] [PMC]

163.

Sandoz PA, Kuhnigk K, Szabo EK, Thunberg S, Erikson E, Sandström N, et al. Modulation of lytic molecules restrain serial killing in γδ T lymphocytes. Nat Commun. 2023;14:6035. [DOI] [PubMed] [PMC]

164.

Nakajima H, Tomiyama H, Takiguchi M. Inhibition of gamma delta T cell recognition by receptors for MHC class I molecules. J Immunol. 1995;155:4139–42. [PubMed]

165.

Carena I, Shamshiev A, Donda A, Colonna M, Libero GD. Major histocompatibility complex class I molecules modulate activation threshold and early signaling of T cell antigen receptor-gamma/delta stimulated by nonpeptidic ligands. J Exp Med. 1997;186:1769–74. [DOI] [PubMed] [PMC]

166.

Cazzetta V, Bruni E, Terzoli S, Carenza C, Franzese S, Piazza R, et al. NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions. Cell Rep. 2021;37:109871. [DOI] [PubMed]

167.

Catafal-Tardos E, Dachicourt L, Baglioni MV, Fares da Silva MGF, Secci D, Donia M, et al. Dynamics of checkpoint receptors in γδ T cell subsets are associated with clinical response during anti-PD-1 immunotherapies. EMBO Mol Med. 2026;18:91–119. [DOI] [PubMed] [PMC]

168.

Ou L, Wang H, Huang H, Zhou Z, Lin Q, Guo Y, et al. Preclinical platforms to study therapeutic efficacy of human γδ T cells. Clin Transl Med. 2022;12:e814. [DOI] [PubMed] [PMC]

169.

Guillamón CF, Martínez-Sánchez MV, Gimeno L, Campillo JA, Server-Pastor G, Martínez-García J, et al. Activating KIRs on Educated NK Cells Support Downregulation of CD226 and Inefficient Tumor Immunosurveillance. Cancer Immunol Res. 2019;7:1307–17. [DOI] [PubMed]

170.

Chen C, Busson M, Rocha V, Appert ML, Lepage V, Dulphy N, et al. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplant. 2006;38:437–44. [DOI] [PubMed]

171.

Feng J, Garrity D, Call ME, Moffett H, Wucherpfennig KW. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity. 2005;22:427–38. [DOI] [PubMed] [PMC]

172.

Qu G, Wang S, Zhou Z, Jiang D, Liao A, Luo J. Comparing Mouse and Human Tissue-Resident γδ T Cells. Front Immunol. 2022;13:891687. [DOI] [PubMed] [PMC]

173.

McDonald BD, Jabri B, Bendelac A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2018;18:514–25. [DOI] [PubMed] [PMC]

174.

Fichtner AS, Ravens S, Prinz I. Human γδ TCR Repertoires in Health and Disease. Cells. 2020;9:800. [DOI] [PubMed] [PMC]

175.

Karunakaran MM, Göbel TW, Starick L, Walter L, Herrmann T. Vγ9 and Vδ2 T cell antigen receptor genes and butyrophilin 3 (BTN3) emerged with placental mammals and are concomitantly preserved in selected species like alpaca (Vicugna pacos). Immunogenetics. 2014;66:243–54. [DOI] [PubMed]

176.

Papadopoulou M, Sanchez Sanchez G, Vermijlen D. Innate and adaptive γδ T cells: How, when, and why. Immunol Rev. 2020;298:99–116. [DOI] [PubMed]

177.

Nattress CB, O’Sullivan R, Fowler D, Hutton C, Vlckova P, Sufi J, et al. Phenoscaping Reveals Multimodal γδ T-cell Cytotoxicity as a Strategy to Overcome Cancer Cell-Mediated Immunomodulation. Cancer Res. 2025;85:4415–32. [DOI] [PubMed] [PMC]

178.

Petitpas C, Mitoyan L, Thevin V, Martin M, Hernandez-Vargas H, Chevrier V, et al. Injury and inflammation promote cancer progression at the anorectal junction. Cell Rep. 2025;44:116552. [DOI] [PubMed]

179.

van Renterghem AWJ, Parra-Martinez M, Witsen M, Verkerk K, Steur M, Zeverijn LJ, et al. Liver metastases dampen IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer. Cell Rep Med. 2026;7:102579. [DOI] [PubMed] [PMC]

180.

Pscheid R, Drent E, Wienke J, Strijker JGM, Throsby M, Molenaar JJ. Three-Dimensional Modeling of Solid Tumors and Their Microenvironment to Evaluate T Cell Therapy Efficacy In Vitro. J Immunol. 2023;211:229–40. [DOI] [PubMed]

181.

Di Mascolo D, Varesano S, Benelli R, Mollica H, Salis A, Zocchi MR, et al. Nanoformulated Zoledronic Acid Boosts the Vδ2 T Cell Immunotherapeutic Potential in Colorectal Cancer. Cancers (Basel). 2019;12:104. [DOI] [PubMed] [PMC]

182.

Tardito S, Matis S, Zocchi MR, Benelli R, Poggi A. Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance. Int J Mol Sci. 2024;25:7131. [DOI] [PubMed] [PMC]

183.

Zhou J, Wu M, Yang G. Decoding γδ T cell anticancer therapies: integrating CRISPR screens with tumor organoids. Signal Transduct Target Ther. 2023;8:423. [DOI] [PubMed] [PMC]

184.

Gunti S, Hoke ATK, Vu KP, London NR Jr. Organoid and Spheroid Tumor Models: Techniques and Applications. Cancers (Basel). 2021;13:874. [DOI] [PubMed] [PMC]

185.

Ishiguro T, Ohata H, Sato A, Yamawaki K, Enomoto T, Okamoto K. Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications. Cancer Sci. 2017;108:283–9. [DOI] [PubMed] [PMC]

186.

Shukla P, Yeleswarapu S, Heinrich MA, Prakash J, Pati F. Mimicking tumor microenvironment by 3D bioprinting: 3D cancer modeling. Biofabrication. 2022;14. [DOI] [PubMed]

187.

Ahmad Zawawi SS, Salleh EA, Musa M. Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening. Explor Target Antitumor Ther. 2024;5:409–31. [DOI] [PubMed] [PMC]

188.

Qin X, Sufi J, Vlckova P, Kyriakidou P, Acton SE, Li VSW, et al. Cell-type-specific signaling networks in heterocellular organoids. Nat Methods. 2020;17:335–42. [DOI] [PubMed] [PMC]

189.

Sufi J, Qin X, Rodriguez FC, Bu YJ, Vlckova P, Zapatero MR, et al. Multiplexed single-cell analysis of organoid signaling networks. Nat Protoc. 2021;16:4897–918. [DOI] [PubMed]

190.

Zunder ER, Finck R, Behbehani GK, Amir el-AD, Krishnaswamy S, Gonzalez VD, et al. Palladium-based mass tag cell barcoding with a doublet-filtering scheme and single-cell deconvolution algorithm. Nat Protoc. 2015;10:316–33. [DOI] [PubMed] [PMC]

191.

Qin X, Cardoso Rodriguez F, Sufi J, Vlckova P, Claus J, Tape CJ. An oncogenic phenoscape of colonic stem cell polarization. Cell. 2023;186:5554–68.e18. [DOI] [PubMed]

192.

Ramos Zapatero M, Tong A, Opzoomer JW, O’Sullivan R, Cardoso Rodriguez F, Sufi J, et al. Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses. Cell. 2023;186:5606–19.e24. [DOI] [PubMed]

193.

Sargenti A, Musmeci F, Bacchi F, Delprete C, Cristaldi DA, Cannas F, et al. Physical Characterization of Colorectal Cancer Spheroids and Evaluation of NK Cell Infiltration Through a Flow-Based Analysis. Front Immunol. 2020;11:564887. [DOI] [PubMed] [PMC]

194.

Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, et al. Commensal Microbiota Promote Lung Cancer Development via γδ T Cells. Cell. 2019;176:998–1013.e16. [DOI] [PubMed] [PMC]

195.

Noble A, Pring ET, Durant L, Man R, Dilke SM, Hoyles L, et al. Altered immunity to microbiota, B cell activation and depleted γδ/resident memory T cells in colorectal cancer. Cancer Immunol Immunother. 2022;71:2619–29. [DOI] [PubMed] [PMC]

196.

Rezende RM, Cox LM, Moreira TG, Liu S, Boulenouar S, Dhang F, et al. Gamma-delta T cells modulate the microbiota and fecal micro-RNAs to maintain mucosal tolerance. Microbiome. 2023;11:32. [DOI] [PubMed] [PMC]

197.

Zhu D, Ren X, Xie W, Chen J, Liang S, Jiang M, et al. Potential of gamma/delta T cells for solid tumor immunotherapy. Front Immunol. 2024;15:1466266. [DOI] [PubMed] [PMC]

198.

Hayday A, Dechanet-Merville J, Rossjohn J, Silva-Santos B. Cancer immunotherapy by γδ T cells. Science. 2024;386:eabq7248. [DOI] [PubMed] [PMC]

199.

Yazdanifar M, Barbarito G, Bertaina A, Airoldi I. γδ T Cells: The Ideal Tool for Cancer Immunotherapy. Cells. 2020;9:1305. [DOI] [PubMed] [PMC]

200.

Zhao Y, Dong P, He W, Zhang J, Chen H. γδ T cells: Major advances in basic and clinical research in tumor immunotherapy. Chin Med J (Engl). 2024;137:21–33. [DOI] [PubMed] [PMC]

201.

Du SH, Li Z, Chen C, Tan WK, Chi Z, Kwang TW, et al. Co-Expansion of Cytokine-Induced Killer Cells and Vγ9Vδ2 T Cells for CAR T-Cell Therapy. PLoS One. 2016;11:e0161820. [DOI] [PubMed] [PMC]

202.

Ang WX, Ng YY, Xiao L, Chen C, Li Z, Chi Z, et al. Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts. Mol Ther Oncolytics. 2020;17:421–30. [DOI] [PubMed] [PMC]

203.

Portillo AL, Mehboob M, Snyder G, Moinuddin A, Ritchie TM, Balint E, et al. IL-21-reprogrammed Vδ1 T cells exert killing against solid tumors which is enhanced by CAR arming for off-the-shelf immunotherapy. Oncoimmunology. 2025;14:2562210. [DOI] [PubMed] [PMC]

204.

van Diest E, Hernández López P, Meringa AD, Vyborova A, Karaiskaki F, Heijhuurs S, et al. Gamma delta TCR anti-CD3 bispecific molecules (GABs) as novel immunotherapeutic compounds. J Immunother Cancer. 2021;9:e003850. [DOI] [PubMed] [PMC]

205.

de Bruin RCG, Veluchamy JP, Lougheed SM, Schneiders FL, Lopez-Lastra S, Lameris R, et al. A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells. Oncoimmunology. 2017;7:e1375641. [DOI] [PubMed] [PMC]

206.

Devaud C, Rousseau B, Netzer S, Pitard V, Paroissin C, Khairallah C, et al. Anti-metastatic potential of human Vδ1(+) γδ T cells in an orthotopic mouse xenograft model of colon carcinoma. Cancer Immunol Immunother. 2013;62:1199–210. [DOI] [PubMed] [PMC]

207.

Bustos X, Snedal S, Tordesillas L, Pelle E, Abate-Daga D. γδ T Cell-Based Adoptive Cell Therapies Against Solid Epithelial Tumors. Cancer J. 2022;28:270–7. [DOI] [PubMed] [PMC]

208.

Agbuduwe C, Maher J, Anderson J. Harnessing the immunotherapeutic potentials of gamma delta T cells against hematological malignancies. Hemasphere. 2025;9:e70182. [DOI] [PubMed] [PMC]

209.

Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 2021;14:101174. [DOI] [PubMed] [PMC]

210.

Siegel RL, Wagle NS, Star J, Kratzer TB, Smith RA, Jemal A. Colorectal cancer statistics, 2026. CA Cancer J Clin. 2026;76:e70067. [DOI] [PubMed] [PMC]

211.

Murphy CC, Zaki TA. Changing epidemiology of colorectal cancer - birth cohort effects and emerging risk factors. Nat Rev Gastroenterol Hepatol. 2024;21:25–34. [DOI] [PubMed]

212.

Matsuda T, Fujimoto A, Igarashi Y. Colorectal Cancer: Epidemiology, Risk Factors, and Public Health Strategies. Digestion. 2025;106:91–9. [DOI] [PubMed]

213.

Zhou J, Yang Q, Zhao S, Sun L, Li R, Wang J, et al. Evolving landscape of colorectal cancer: Global and regional burden, risk factor dynamics, and future scenarios (the Global Burden of Disease 1990-2050). Ageing Res Rev. 2025;104:102666. [DOI] [PubMed]

214.

Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72:338–44. [DOI] [PubMed]

215.

Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6. [DOI] [PubMed] [PMC]

216.

Das A, Chetta PM, Zhang ML. Molecular Advances in Gastrointestinal Pathology. Semin Diagn Pathol. 2026;43:150990. [DOI] [PubMed]

217.

Keivany MR, Shojae Asrami E, Besharatloo M, Latifi H, Barjasteh AH. Advances in immunotherapy for colorectal cancer: overcoming resistance in mismatch repair-proficient tumors. Cancer Cell Int. 2026;26:151. [DOI] [PubMed] [PMC]

218.

Sahin IH, Saridogan T, Kim R. Predictive biomarkers for immune checkpoint inhibition for patients with colorectal cancer: a comprehensive review. Immunotherapy. 2025;17:727–34. [DOI] [PubMed] [PMC]

219.

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. 2025;15:1440830. [DOI] [PubMed] [PMC]

220.

Chen E, Zhou W. Immunotherapy in microsatellite-stable colorectal cancer: Strategies to overcome resistance. Crit Rev Oncol Hematol. 2025;212:104775. [DOI] [PubMed]

221.

Trahearn N, Sakr C, Banerjee A, Lee SH, Baker AM, Kocher HM, et al. Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome. J Pathol. 2025;265:198–210. [DOI] [PubMed] [PMC]

222.

Lee KS, Kwak Y, Ahn S, Shin E, Oh HK, Kim DW, et al. Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer. Cancer Immunol Immunother. 2017;66:927–39. [DOI] [PubMed] [PMC]

223.

Sun F, Yao F, Zeng C, Zhao Y, Liang B, Li S, et al. Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation. J Immunother Cancer. 2025;13:e010126. [DOI] [PubMed] [PMC]

224.

Ten Hoorn S, de Back TR, Sommeijer DW, Vermeulen L. Clinical Value of Consensus Molecular Subtypes in Colorectal Cancer: A Systematic Review and Meta-Analysis. J Natl Cancer Inst. 2022;114:503–16. [DOI] [PubMed] [PMC]

225.

Kantha A, Das D, Pai E, Kumar T, Pandey M. Consensus Molecular Subtypes (CMS) Classification: a progress towards Subtype-Driven treatments in colorectal cancer. World J Surg Oncol. 2025;24:1. [DOI] [PubMed] [PMC]

226.

Zhang J, Zhu H, Liu W, Miao J, Mao Y, Li Q. Prognostic and predictive molecular biomarkers in colorectal cancer. Front Oncol. 2025;15:1532924. [DOI] [PubMed] [PMC]

227.

Anderson P, Aptsiauri N, Ruiz-Cabello F, Garrido F. HLA class I loss in colorectal cancer: implications for immune escape and immunotherapy. Cell Mol Immunol. 2021;18:556–65. [DOI] [PubMed] [PMC]

228.

Barsoum IB, Koti M, Siemens DR, Graham CH. Mechanisms of hypoxia-mediated immune escape in cancer. Cancer Res. 2014;74:7185–90. [DOI] [PubMed]

229.

Yan J. Antitumor γδ T cells need oxygen to function. Nat Immunol. 2021;22:268–9. [DOI] [PubMed] [PMC]

230.

He W, Hu Y, Chen D, Li Y, Ye D, Zhao Q, 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. 2022;12:e800. [DOI] [PubMed] [PMC]

231.

Jonescheit H, Oberg HH, Gonnermann D, Hermes M, Sulaj V, Peters C, et al. Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells. Cells. 2020;9:1140. [DOI] [PubMed] [PMC]

232.

Piñeiro Fernández J, Luddy KA, Harmon C, O’Farrelly C. Hepatic Tumor Microenvironments and Effects on NK Cell Phenotype and Function. Int J Mol Sci. 2019;20:4131. [DOI] [PubMed] [PMC]

233.

Lockhart A, Mucida D, Bilate AM. Intraepithelial Lymphocytes of the Intestine. Annu Rev Immunol. 2024;42:289–316. [DOI] [PubMed] [PMC]

234.

Konjar Š, Ferreira C, Carvalho FS, Figueiredo-Campos P, Fanczal J, Ribeiro S, et al. Intestinal tissue-resident T cell activation depends on metabolite availability. Proc Natl Acad Sci U S A. 2022;119:e2202144119. [DOI] [PubMed] [PMC]

235.

Dunne PD, Arends MJ. Molecular pathological classification of colorectal cancer-an update. Virchows Arch. 2024;484:273–85. [DOI] [PubMed] [PMC]

236.

Poggi A, Matis S, Uras CRM, Raffaghello L, Benelli R, Zocchi MR. The Role of LAIR1 as a Regulatory Receptor of Antitumor Immune Cell Responses and Tumor Cell Growth and Expansion. Biomolecules. 2025;15:866. [DOI] [PubMed] [PMC]

237.

Pascoal Ramos MI, van der Vlist M, Meyaard L. Inhibitory pattern recognition receptors: lessons from LAIR1. Nat Rev Immunol. 2025;25:711–24. [DOI] [PubMed]

238.

Costa D, Venè R, Benelli R, Romairone E, Scabini S, Catellani S, et al. Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts. Front Immunol. 2018;9:1150. [DOI] [PubMed] [PMC]

239.

Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, et al. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther. 2021;6:218. [DOI] [PubMed] [PMC]

240.

Poggi A, Tomasello E, Revello V, Nanni L, Costa P, Moretta L. p40 molecule regulates NK cell activation mediated by NK receptors for HLA class I antigens and TCR-mediated triggering of T lymphocytes. Int Immunol. 1997;9:1271–9. [DOI] [PubMed]

241.

Du B, Qin J, Lin B, Zhang J, Li D, Liu M. CAR-T therapy in solid tumors. Cancer Cell. 2025;43:665–79. [DOI] [PubMed]

242.

Liu Y, An L, Huang R, Xiong J, Yang H, Wang X, et al. Strategies to enhance CAR-T persistence. Biomark Res. 2022;10:86. [DOI] [PubMed] [PMC]

243.

Wang CQ, Lim PY, Tan AH. Gamma/delta T cells as cellular vehicles for anti-tumor immunity. Front Immunol. 2024;14:1282758. [DOI] [PubMed] [PMC]

244.

Poggi A, Zocchi MR, Costa P, Ferrero E, Borsellino G, Placido R, et al. IL-12-mediated NKRP1A up-regulation and consequent enhancement of endothelial transmigration of V delta 2+ TCR gamma delta+ T lymphocytes from healthy donors and multiple sclerosis patients. J Immunol. 1999;162:4349–54. [PubMed]

245.

Poggi A, Carosio R, Fenoglio D, Brenci S, Murdaca G, Setti M, et al. Migration of V delta 1 and V delta 2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat. Blood. 2004;103:2205–13. [DOI] [PubMed]

246.

Poggi A, Zocchi MR, Carosio R, Ferrero E, Angelini DF, Galgani S, et al. Transendothelial migratory pathways of V delta 1+TCR gamma delta+ and V delta 2+TCR gamma delta+ T lymphocytes from healthy donors and multiple sclerosis patients: involvement of phosphatidylinositol 3 kinase and calcium calmodulin-dependent kinase II. J Immunol. 2002;168:6071–7. [DOI] [PubMed]

247.

Huang X, Feng D, Mitra S, Andretta ES, Hooshdaran NB, Ghelani AP, et al. Opposing functions of distinct regulatory T cell subsets in colorectal cancer. Immunity. 2026;59:145–60.e9. [DOI] [PubMed] [PMC]

248.

Chen Y, Liu T, Min G, Wang C, Xi D, Jiang L. Single-cell transcriptome analysis reveals regulatory programs associated with tumor resistance during immunotherapy in colorectal cancer. Int J Surg. 2026;112:694–708. [DOI] [PubMed] [PMC]

249.

Chen Z, Song W, Li Q, Li C, Wen W, Huyghe JR, et al. Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility. Nat Commun. 2026;17:1377. [DOI] [PubMed] [PMC]

250.

Li S, Simoni Y, Becht E, Loh CY, Li N, Lachance D, et al. Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer. Cell Rep Med. 2020;1:100039. [DOI] [PubMed] [PMC]

251.

Gherardin NA, Waldeck K, Caneborg A, Martelotto LG, Balachander S, Zethoven M, et al. γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival. Cancer Immunol Res. 2021;9:612–23. [DOI] [PubMed]

252.

Rice MT, von Borstel A, Chevour P, Awad W, Howson LJ, Littler DR, et al. Recognition of the antigen-presenting molecule MR1 by a Vδ3⁺ γδ T cell receptor. Proc Natl Acad Sci U S A. 2021;118:e2110288118. [DOI] [PubMed] [PMC]

253.

Maerz MD, Cross DL, Seshadri C. Functional and biological implications of clonotypic diversity among human donor-unrestricted T cells. Immunol Cell Biol. 2024;102:474–86. [DOI] [PubMed] [PMC]

254.

McWilliam HE, Villadangos JA. MR1: a multi-faceted metabolite sensor for T cell activation. Curr Opin Immunol. 2020;64:124–9. [DOI] [PubMed]

255.

Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World J Gastrointest Surg. 2023;15:495–519. [DOI] [PubMed] [PMC]

256.

Huo Z, Liu G, Li J. Recent research progress and clinical status of immunotherapy for colorectal cancer. J Adv Res. 2026;82:729–50. [DOI] [PubMed] [PMC]

257.

Scott AJ, Alexander JL, Merrifield CA, Cunningham D, Jobin C, Brown R, et al. International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis. Gut. 2019;68:1624–32. [DOI] [PubMed] [PMC]

258.

Yu Y, Zhao W, Yang M, Wu B, Yuan X. Tumor-Promoting Gut Microbes in Colorectal Cancer: Mechanisms and Translational Perspectives. Int J Med Sci. 2026;23:63–75. [DOI] [PubMed] [PMC]

259.

Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71. [DOI] [PubMed] [PMC]

260.

Saleh OM, Albakri KA, Alabdallat YJ, Dajani MH, El Gazzar WB. The safety and efficacy of CAR-T cells in the treatment of prostate cancer: review. Biomarkers. 2022;27:22–34. [DOI] [PubMed]

261.

Jeyakumar N, Smith M. Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL. Front Immunol. 2022;13:887866. [DOI] [PubMed] [PMC]

262.

Tao Y, Lu Y, Yu B, Wang Y. Molecular glue meets antibody: next-generation antibody-drug conjugates. Trends Pharmacol Sci. 2025;46:520–34. [DOI] [PubMed]