TIGIT immunosuppressive role in female reproductive system malignant neoplasms: from mechanism to therapy

Introduction. Malignant neoplasms of the female reproductive system (ovarian, endometrial, and cervical cancers) account for a significant proportion of female oncology morbidity and mortality. Standard treatment methods, including surgery, chemotherapy, and radiotherapy, show limited efficacy in recurrent and drug-resistant tumors. The development of immunotherapy, particularly immune checkpoint inhibitors (ICI), has opened new therapeutic avenues; however, their clinical effectiveness in gynecologic oncology remains suboptimal. In connection with this, it has increased an interest in novel targets, notably TIGIT (T-cell immunoglobulin and ITIM domain), a co-inhibitory receptor expressed on T-cells and natural killer cells (NK-cells), which plays a key role in establishing an immunosuppressive tumor microenvironment.

Aim: to systematize current data on the biological function of TIGIT and relevant ligands, its role in immunosuppression in malignant neoplasms of the female reproductive system as well as evaluate a therapeutic potential of its blockade during a personalized immunotherapy.

Materials and Methods. This review was conducted according to the PRISMA methodology. There was performed a systematic literature search for publications from 2013 to 2024 in the databases PubMed/MEDLINE, Scopus, Web of Science, Embase, Google Scholar, and ClinicalTrials.gov. A total of 91 scientific sources and 7 registered clinical trials were included. Original studies, meta-analyses, reviews, guidelines, and clinical trial reports were analyzed.

Results. TIGIT interacts with several ligands (CD155, CD112, Nectin-4, Fap2), leading to suppression of NK-cells and CD8+ T-cells activity, macrophage polarization toward M2 phenotype, activation of regulatory T-cells (Treg), and impaired antigen presentation. TIGIT is co-expressed with PD-1 (programmed cell death protein 1) and CD96, forming a suppressive signaling network. Its elevated expression is associated with disease progression in ovarian, endometrial, and cervical cancers, reduced cytotoxicity of tumor-infiltrating lymphocytes (TIL), and poor prognosis. TIGIT blockade, especially in combination with PD-1/PD-L1 (programmed cell death ligand 1), restores effector cell function and enhances antitumor immunity in preclinical and clinical studies.

Conclusion. TIGIT is a promising immunotherapeutic target in malignant neoplasms of the female reproductive system. Its blockade may improve treatment outcomes in patients with recurrent and resistant cancert ypes. Combined approaches involving anti-TIGIT agents require further clinical validation but even today they offer new directions in targeted therapy and personalized management in gynecologic oncology.

1. Chernobrovkina A.E. The incidence of malignant tumors of the female reproductive system in St. Petersburg. [Zabolevaemost' zlokachestvennymi novoobrazovaniyami zhenskoj polovoj sfery naseleniya Sankt-Peterburga]. Zdorov'e naseleniya i sreda obitaniya – ZNiSO. 2022;30(1):29–35. (In Russ.).https://doi.org/10.35627/2219-5238/2022-30-1-29-35.

2. Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

3. Song Y., Zhang Y. Research progress of neoantigens in gynecologic cancers. Int Immunopharmacol. 2022;112:109236. https://doi.org/10.1016/j.intimp.2022.109236.

4. Peng H., He X., Wang Q. Immune checkpoint blockades in gynecological cancers: a review of clinical trials. Acta Obstet Gynecol Scand. 2022;101(9):941–51. https://doi.org/10.1111/aogs.14412.

5. Shubnikova E.V., Bukatina T.M., Velts N.Yu. et al. Immune response checkpoint inhibitors: new risks of a new class of antitumor agents. [Ingibitory kontrol'nyh tochek immunnogo otveta: novye riski novogo klassa protivoopuholevyh sredstv]. Bezopasnost' i risk farmakoterapii. 2020;8(1):9–22. (In Russ.). https://doi.org/10.30895/2312-7821-2020-8-1-9-22.

6. Gaptulbarova K.A., Tsyganov M.M., Ibragimova M.K. et al. Efficiency in different immunotherapy of cancer: literature review. [Effektivnost' immunoterapii pri raznyh zlokachestvennyh novoobrazovaniyah: obzor literatury]. Uspekhi molekulyarnoj onkologii. 2021;8(4):8–20. (In Russ.). https://doi.org/10.17650/2313-805X-2021-8-4-8-20.

7. Petitprez F., Meylan M., de Reyniès A. et al. The tumor microenvironment in the response to immune checkpoint blockade therapies. Front Immunol. 2020;11:784. https://doi.org/10.3389/fimmu.2020.00784.

8. Drakes M.L., Czerlanis C.M., Stiff P.J. Immune ccheckpoint blockade in gynecologic cancers: state of affairs. Cancers (Basel). 2020;12(11):3301. https://doi.org/10.3390/cancers12113301.

9. Mustafina D.A., Bagautdinova A.N., Zinatullina M.M. et al. The role of immune checkpoint inhibitors in the development and treatment of infectious processes. [Rol' ingibitorov immunnyh kontrol'nyh tochek v razvitii i lechenii infekcionnyh processov]. Klinicheskaya praktika. 2024;15(1):91–106. (In Russ.). https://doi.org/10.17816/clinpract627504.

10. Chauvin J.M., Zarour H.M. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8(2):e000957. https://doi.org/10.1136/jitc-2020-000957.

11. Tang W., Chen J., Ji T., Cong X. TIGIT, a novel immune checkpoint therapy for melanoma. Cell Death Dis. 2023;14(7):466. https://doi.org/10.1038/s41419-023-05961-3.

12. Yu X., Harden K., Gonzalez L.C. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48–57. https://doi.org/10.1038/ni.1674.

13. Chiang E.Y., Mellman I. TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy. J Immunother Cancer. 2022;10(4):e004711. https://doi.org/10.1136/jitc-2022-004711.

14. Stengel K.F., Harden-Bowles K., Yu X. et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci U S A. 2012;109(14):5399–404. https://doi.org/10.1073/pnas.1120606109.

15. Manieri N.A., Chiang E.Y., Grogan J.L. TIGIT: a key inhibitor of the cancer immunity cycle. Trends Immunol. 2017;38(1):20–8. https://doi.org/10.1016/j.it.2016.10.002.

16. Reches A., Ophir Y., Stein N. et al. Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. J Immunother Cancer. 2020;8(1):e000266. https://doi.org/10.1136/jitc-2019-000266.

17. Gur C., Ibrahim Y., Isaacson B. et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015;42(2):344–55. https://doi.org/10.1016/j.immuni.2015.01.010.

18. Zhou R., Chen S., Wu Q. et al. CD155 and its receptors in cancer immune escape and immunotherapy. Cancer Lett. 2023;573:216381. https://doi.org/10.1016/j.canlet.2023.216381.

19. Jin H.S., Park Y. Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy. BMB Rep. 2021;54(1):2–11. https://doi.org/10.5483/BMBRep.2021.54.1.229.

20. Zeng T., Cao Y., Jin T. et al. The CD112R/CD112 axis: a breakthrough in cancer immunotherapy. J Exp Clin Cancer Res. 2021;40(1):285. https://doi.org/10.1186/s13046-021-02053-y.

21. Son Y., Lee B., Choi Y.J. et al. Nectin-2 (CD112) is expressed on outgrowth endothelial cells and regulates cell proliferation and angiogenic function. PLoS One. 2016;11(9):e0163301. https://doi.org/10.1371/journal.pone.0163301.

22. Deuss F.A., Gully B.S., Rossjohn J., Berry R. Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT). J Biol Chem. 2017;292(27):11413–22. https://doi.org/10.1074/jbc.M117.786483.

23. Wu B., Zhong C., Lang Q. et al. Poliovirus receptor (PVR)-like protein cosignaling network: new opportunities for cancer immunotherapy. J Exp Clin Cancer Res. 2021;40(1):267. https://doi.org/10.1186/s13046-021-02068-5.

24. Yue C., Gao S., Li S. et al. TIGIT as a promising therapeutic target in autoimmune diseases. Front Immunol. 2022;13:911919. https://doi.org/10.3389/fimmu.2022.911919.

25. Bouleftour W., Guillot A., Magne N. The anti-nectin 4: a promising tumor cells target. A systematic review. Mol Cancer Ther. 2022;21(4):493–501. https://doi.org/10.1158/1535-7163.MCT-21-0846.

26. Braun M., Aguilera A.R., Sundarrajan A. et al. CD155 on tumor cells drives resistance to immunotherapy by Inducing the degradation of the activating receptor CD226 in CD8+ T cells. Immunity. 2020;53(4):805–823.e15. https://doi.org/10.1016/j.immuni.2020.09.010.

27. Viot J., Abdeljaoued S., Vienot A. et al. CD8+ CD226high T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery. Cell Mol Immunol. 2023;20(4):365–78. https://doi.org/10.1038/s41423-023-00978-2.

28. Weulersse M., Asrir A., Pichler A.C. et al. Eomes-dependent loss of the co-activating receptor CD226 restrains CD8+ T cell aAnti-tumor functions and limits the efficacy of cancer immunotherapy. Immunity. 2020;53(4):824-839.e10. https://doi.org/10.1016/j.immuni.2020.09.006.

29. Shibuya A., Shibuya K. DNAM-1 versus TIGIT: competitive roles in tumor immunity and inflammatory responses. Int Immunol. 2021;33(12):687–92. https://doi.org/10.1093/intimm/dxab085.

30. Stanietsky N., Simic H., Arapovic J. et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2009;106(42):17858–63. https://doi.org/10.1073/pnas.0903474106.

31. Johnston R.J., Comps-Agrar L., Hackney J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923–37. https://doi.org/10.1016/j.ccell.2014.10.018.

32. Banta K.L., Xu X., Chitre A.S. et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity. 2022;55(3):512–26. https://doi.org/10.1016/j.immuni.2022.02.005.

33. Feng S, Isayev O, Werner J, Bazhin AV. CD96 as a potential immune regulator in cancers. Int J Mol Sci. 2023;24(2):1303. https://doi.org/10.3390/ijms24021303.

34. Georgiev H., Ravens I., Papadogianni G., Bernhardt G. Coming of age: CD96 emerges as modulator of immune responses. Front Immunol. 2018;9:1072. https://doi.org/10.3389/fimmu.2018.01072.

35. Chiang E.Y., de Almeida P.E., de Almeida Nagata D.E. et al. CD96 functions as a co-stimulatory receptor to enhance CD8+ T cell activation and effector responses. Eur J Immunol. 2020;50(6):891–902. https://doi.org/10.1002/eji.201948405.

36. Zhu Y., Paniccia A., Schulick A.C. et al. Identification of CD112R as a novel checkpoint for human T cells. J Exp Med. 2016;213(2):167–76. https://doi.org/10.1084/jem.20150785.

37. Whelan S., Ophir E., Kotturi M.F. et al. PVRIG and PVRL2 are induced in cancer and inhibit CD8+ T-cell function. Cancer Immunol Res. 2019;7(2):257–68. https://doi.org/10.1158/2326-6066.CIR-18-0442.

38. Chu X., Tian W., Wang Z. et al. Correction: co-inhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: mechanisms and clinical trials. Mol Cancer. 2023;22(1):101. https://doi.org/10.1186/s12943-023-01812-z.

39. Paijens S.T., Vledder A., de Bruyn M., Nijman H.W. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021;18(4):842–59. https://doi.org/10.1038/s41423-020-00565-9.

40. Liu S., Zhang H., Li M. et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 2013;20(3):456–64. https://doi.org/10.1038/cdd.2012.141.

41. Li M., Xia P., Du Y. et al. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling. J Biol Chem. 2014;289(25):17647–57. https://doi.org/10.1074/jbc.M114.572420.

42. Kumar S. Natural killer cell cytotoxicity and its regulation by inhibitory receptors. Immunology. 2018;154(3):383–93. https://doi.org/10.1111/imm.12921.

43. Joller N., Hafler J.P., Brynedal B. et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186(3):1338–42. https://doi.org/10.4049/jimmunol.1003081.

44. He W., Zhang H., Han F. et al. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res. 2017;77(22):6375–88. https://doi.org/10.1158/0008-5472.CAN-17-0381.

45. Li J., Zhou J., Huang H. et al. Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): aA novel population in the tumour microenvironment and immunotherapy target. Clin Transl Med. 2023;13(2):e1199. https://doi.org/10.1002/ctm2.1199.

46. Saraiva M., Vieira P., O'Garra A. Biology and therapeutic potential of interleukin-10. J Exp Med. 2020;217(1):e20190418. https://doi.org/10.1084/jem.20190418.

47. Lucca L.E., Dominguez-Villar M. Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol. 2020;20(11):680–93. https://doi.org/10.1038/s41577-020-0296-3.

48. Cortez J.T., Montauti E., Shifrut E. et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature. 2020;582(7812):416–20. https://doi.org/10.1038/s41586-020-2246-4.

49. Zhang Y., Maksimovic J., Naselli G. et al. Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood. 2013;122(16):2823–36. https://doi.org/10.1182/blood-2013-02-481788.

50. Joller N., Lozano E., Burkett P.R. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569–81. https://doi.org/10.1016/j.immuni.2014.02.012.

51. Lucca L.E., Axisa P.P., Singer E.R. et al. TIGIT signaling restores suppressor function of Th1 Tregs. JCI Insight. 2019;4(3):e124427. https://doi.org/10.1172/jci.insight.124427.

52. Preillon J., Cuende J., Rabolli V. et al. Restoration of T-cell effector function, depletion of Tregs, and direct killing of tumor cells: the multiple mechanisms of action of a-TIGIT antagonist antibodies. Mol Cancer Ther. 2021;20(1):121–31. https://doi.org/10.1158/1535-7163.MCT-20-0464.

53. Jayasingam S.D., Citartan M., Thang T.H. et al. Evaluating the polarization of tumor-associated macrophages into M1 and M2 phenotypes in human cancer tissue: technicalities and challenges in routine clinical practice. Front Oncol. 2020;9:1512. https://doi.org/10.3389/fonc.2019.01512.

54. Brauneck F., Fischer B., Witt M. et al. TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis. J Immunother Cancer. 2022;10(12):e004794. https://doi.org/10.1136/jitc-2022-004794.

55. Noguchi Y., Maeda A., Lo P.C. et al. Human TIGIT on porcine aortic endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity. Immunobiology. 2019;224(5):605–13. https://doi.org/10.1016/j.imbio.2019.07.008.

56. Mao L., Xiao Y., Yang Q.C. et al. TIGIT/CD155 blockade enhances anti-PD-L1 therapy in head and neck squamous cell carcinoma by targeting myeloid-derived suppressor cells. Oral Oncol. 2021;121:105472. https://doi.org/10.1016/j.oraloncology.2021.105472.

57. Sarhan D., Cichocki F., Zhang B. et al. Adaptive NK cells with low TIGIT expression are inherently resistant to myeloid-derived suppressor cells. Cancer Res. 2016;76(19):5696–706. https://doi.org/10.1158/0008-5472.CAN-16-0839.

58. Zou Y., Xu Y., Chen X., Zheng L. Advances in the application of immune checkpoint inhibitors in gynecological tumors. Int Immunopharmacol. 2023;117:109774. https://doi.org/10.1016/j.intimp.2023.109774.

59. Sharma P., Goswami S., Raychaudhuri D. et al. Immune checkpoint therapy-current perspectives and future directions. Cell. 2023;186(8):1652–69. https://doi.org/10.1016/j.cell.2023.03.006.

60. Vostrov A.N., Kazakevich V.I., Mitina L.A. et al. Errors of sonography in the diagnosis of the prevalence rate of ovarian cancer. [Oshibki ekhografii v diagnostike rasprostranennosti raka yaichnikov]. Arhiv akusherstva i ginekologii imeni V.F. Snegireva. 2017;4(1):40–4. (In Russ.). https://doi.org/10.18821/2313-8726-2017-4-1-40-44.

61. Lheureux S., Gourley C., Vergote I., Oza A.M. Epithelial ovarian cancer. Lancet. 2019;393(10177):1240–53. https://doi.org/10.1016/S0140-6736(18)32552-2.

62. Pawłowska A., Skiba W., Suszczyk D. et al. The dual blockade of the TIGIT and PD-1/PD-L1 pathway as a new hope for ovarian cancer patients. Cancers (Basel). 2022;14(23):5757. https://doi.org/10.3390/cancers14235757.

63. Pawłowska A., Rekowska A., Kuryło W. et al. Current understanding on why ovarian cancer is resistant to immune checkpoint inhibitors. Int J Mol Sci. 2023;24(13):10859. https://doi.org/10.3390/ijms241310859.

64. Maas R.J., Hoogstad-van Evert J.S., Van der Meer J.M. et al. TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer. Oncoimmunology. 2020;9(1):1843247. https://doi.org/10.1080/2162402X.2020.1843247.

65. Maiorano B.A., Maiorano M.F.P., Lorusso D., Maiello E. Ovarian cancer in the era of immune checkpoint inhibitors: state of the art and future perspectives. Cancers (Basel). 2021;13(17):4438. https://doi.org/10.3390/cancers13174438.

66. Howitt B.E., Strickland K.C., Sholl L.M. et al. Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology. 2017;6(2):e1277308. https://doi.org/10.1080/2162402X.2016.1277308.

67. Yang B., Li X., Zhang W. et al. Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis. Cell Rep Med. 2022;3(12):100856. https://doi.org/10.1016/j.xcrm.2022.100856.

68. Chen F., Xu Y., Chen Y., Shan S. TIGIT enhances CD4+ regulatory T-cell response and mediates immune suppression in a murine ovarian cancer model. Cancer Med. 2020;9(10):3584–91. https://doi.org/10.1002/cam4.2976.

69. Xu J., Fang Y., Chen K. et al. Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer. Clin Cancer Res. 2022;28(16):3590–602. https://doi.org/10.1158/1078-0432.CCR-22-0296.

70. Smazynski J., Hamilton P.T., Thornton S. et al. The immune suppressive factors CD155 and PD-L1 show contrasting expression patterns and immune correlates in ovarian and other cancers. Gynecol Oncol. 2020;158(1):167–77. https://doi.org/10.1016/j.ygyno.2020.04.689.

71. Laumont C.M., Wouters M.C.A., Smazynski J. et al. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39, CD103, and PD-1 in ovarian cancer. Clin Cancer Res. 2021;27(14):4089–100. https://doi.org/10.1158/1078-0432.CCR-20-4394.

72. Brenna E., Pedroza-Pacheco I. Harnessing CXCL13 in ovarian cancer. Nat Rev Immunol. 2022;22(3):145. https://doi.org/10.1038/s41577-022-00683-7.

73. Ozmadenci D., Shankara Narayanan J.S., Andrew J. et al. Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis. Proc Natl Acad Sci U S A. 2022;119(17):e2117065119. https://doi.org/10.1073/pnas.2117065119.

74. KulievaG.Z., Mkrtchyan L.S., Krikunova L.I. et al. Epidemiological aspects of the incidence and mortality of cervical cancer (literature review). [Epidemiologicheskie aspekty zabolevaemosti rakom shejki matki i smertnosti ot nego (obzor literatury)]. Opuholi zhenskoj reproduktivnoj sistemy. 2023;19(3):77–84. (In Russ.) https://doi.org/10.17650/1994-4098-2023-19-3-77-84.

75. Gennigens C., Jerusalem G., Lapaille L. et al. Recurrent or primary metastatic cervical cancer: current and future treatments. ESMO Open. 2022;7(5):100579. https://doi.org/10.1016/j.esmoop.2022.100579.

76. Pivazyan L.G., Unanyan A.L., Davydova Ju.D. et al. Cervical cancer prevention and screening: a review of international clinical guidelines. [Profilaktika i skrining raka shejki matki: obzor mezhdunarodnyh klinicheskih rekomendacij]. Problemy reprodukcii. 2022;28(5):90–9. (In Russ.). https://doi.org/10.17116/repro20222805190.

77. Liu Y., Wu L., Tong R. et al. PD-1/PD-L1 inhibitors in cervical cancer. Front Pharmacol. 2019;10:65. https://doi.org/10.3389/fphar.2019.00065.

78. Feng Y.C., Ji W.L., Yue N. et al. The relationship between the PD-1/PD-L1 pathway and DNA mismatch repair in cervical cancer and its clinical significance. Cancer Manag Res. 2018;10:105–13. https://doi.org/10.2147/CMAR.S152232.

79. Li C., Cang W., Gu Y. et al. The anti-PD-1 era of cervical cancer: achievement, opportunity, and challenge. Front Immunol. 2023;14:1195476. https://doi.org/10.3389/fimmu.2023.1195476.

80. Liu L., Wang A., Liu X. et al. Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer. J Transl Med. 2022;20(1):280. https://doi.org/10.1186/s12967-022-03480.

81. Wang Y., Wang C., Qiu J. et al. Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer. J Immunother Cancer. 2022;10(3):e003667. https://doi.org/10.1136/jitc-2021-003667.

82. Kalampokas E., Giannis G., Kalampokas T. et al. Current approaches to the management of patients with endometrial cancer. Cancers (Basel). 2022;14(18):4500. https://doi.org/10.3390/cancers14184500.

83. Jamieson A., Bosse T., McAlpine J.N. The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer. Ther Adv Med Oncol. 2021;13:17588359211035959. https://doi.org/10.1177/17588359211035959.

84. Rizzo A. Immune checkpoint inhibitors and mismatch repair status in advanced endometrial cancer: elective affinities. J Clin Med. 2022;11(13):3912. https://doi.org/10.3390/jcm11133912.

85. Cancer Genome Atlas Research Network; Kandoth C., Schultz N. et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. https://doi.org/10.1038/nature12113.

86. Mullen M.M., Mutch D.G. Endometrial tumor immune response: predictive biomarker of response to immunotherapy. Clin Cancer Res. 2019;25(8):2366–8. https://doi.org/10.1158/1078-0432.CCR-18-4122.

87. Gargiulo P., Della Pepa C., Berardi S. et al. Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated endometrial cancers: nNew candidates for checkpoint blockade immunotherapy? Cancer Treat Rev. 2016;48:61–8. https://doi.org/10.1016/j.ctrv.2016.06.008.

88. Degos C., Heinemann M., Barrou J. et al. Endometrial tumor microenvironment alters human NK cell recruitment, and resident NK cell phenotype and function. Front Immunol. 2019;10:877. https://doi.org/10.3389/fimmu.2019.00877.

89. Jiang F., Mao M., Jiang S. et al. PD-1 and TIGIT coexpressing CD8 + CD103 + tissue-resident memory cells in endometrial cancer as potential targets for immunotherapy. Int Immunopharmacol. 2024;127:111381. https://doi.org/10.1016/j.intimp.2023.111381.

90. Kim T.W., Bedard P.L., LoRusso P. et al. Anti-TIGIT antibody tiragolumab alone or with atezolizumab in patients with advanced solid tumors: a phase 1a/1b nonrandomized controlled trial. JAMA Oncol. 2023;9(11):1574–82. https://doi.org/10.1001/jamaoncol.2023.3867.

91. Cho B.C., Abreu D.R., Hussein M. et al. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol. 2022;23(6):781–92. https://doi.org/10.1016/S1470-2045(22)00226-1.