THE ROLE OF MECHANICAL PROPERTIES OF T-CELLS IN SHAPING THE IMMUNE RESPONSE

Abstract

Recent studies in immunology highlight the critical role of mechanical factors in shaping the immune response. Mechanoimmunology, as an emerging interdisciplinary field, investigates the influence of mechanical stimuli on immune cell behavior, particularly T-lymphocytes. It has been demonstrated that microenvironment stiffness, mechanical interactions with the extracellular matrix, and changes in membrane tension can modulate T-cell activation, migration, proliferation, and effector functions. An optimal mechanical environment enhances T-cell activity, whereas increased stiffness of the microenvironment and alterations in extracellular matrix properties can reduce their functional capacity. Key molecules such as Piezo 1, integrins, and Yes-associated protein serve as central regulators of mechanotransduction in immune cells. The gradual expansion of knowledge regarding their role in the immune response indicates a high degree of interconnected modulation, forming a system that enables a coordinated reaction to mechanical stimuli. Mechanomodulation alters the intracellular environment, acting as a determinant of the metabolic profile of T-cells. Additionally, studies indicate that mechanosensitive signaling pathways may regulate intercellular interactions and adaptive immune responses, offering broad opportunities for modifying immune reactions. Understanding mechanotransduction mechanisms provides new prospects for the development of therapeutic strategies. Mechanical signals can be leveraged to enhance the efficacy of CAR-T cells by optimizing their activation, proliferation, and infiltration into tumor tissue, which is particularly important in treating malignant neoplasms, especially solid tumors, where CAR-T cell therapy faces significant limitations. Mechanoimmunological approaches are also being explored in the context of autoimmune disease treatment. It is hypothesized that mechanosensitive pathways may regulate excessive T-cell activation, preventing autoimmune processes and pathological hyperactivation of the immune system. Moreover, the development of effective methods for preventing graft-versus-host disease and transplant rejection, as well as strategies for treating chronic infections, remains an important goal. The spectrum of potential pharmacological interventions includes the use of activators and inhibitors of Piezo 1, integrins, and Yes-associated protein. Bioengineering approaches are also being actively developed. One promising direction involves the use of nanomotors for ex vivo T-cell activation, which may improve the efficacy of cellular immunotherapy in various diseases. Furthermore, fine-tuning immune responses through mechanical properties could enable precise regulation of immune activity based on the specific characteristics of pathological processes.

1. Acuto O. T-cell virtuosity in ‘‘knowing thyself”. Front. Immunol., 2024, Vol. 15, 1343575. DOI: 10.3389/fimmu.2024.1343575

2. Alatoom A., ElGindi M., Sapudom J., Teo J. C. M. The T Cell Journey: A Tour de Force. Advanced Biology, 2023, Vol. 7, no. 1, 2200173. DOI: 10.1002/adbi.202200173

3. Angeli V., Lim H. Y. Biomechanical control of lymphatic vessel physiology and functions. Cell. Mol. Immunol., 2023, Vol. 20, no. 9, pp. 1051-1062. DOI: 10.1038/s41423-023-01042-9

4. Bai J., Yan M., Xu Y., Wang Y., Yao Y., Jin P., Zhang Y., Qu Y., Niu L., Li H. YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix. J. Immunother. Cancer, 2024, Vol. 12, no. 11, e010463. DOI: 10.1136/jitc-2024-010463

5. Bergert M., Erzberger A., Desai R. A., Aspalter I. M., Oates A. C., Charras G., Salbreux G., Paluch E. K. Force transmission during adhesion-independent migration. Nat. Cell. Biol., 2015, Vol. 17, no. 4, pp. 524-529. DOI: 10.1038/ncb3134

6. Bertoni A., Alabiso O., Galetto A., Baldanzi G. Integrins in T Cell Physiology. IJMS, 2018, Vol. 19, no. 2, p. 485. DOI: 10.3390/ijms19020485

7. Boesen E. I., Kakalij R. M. Autoimmune-mediated renal disease and hypertension. Clinical Science, 2021, Vol. 135, no. 17, pp. 2165-2196. DOI: 10.1042/CS20200955

8. Brosinsky P., Leister H., Cheng N., Varelas X., Visekruna A., Luu M. Verteporfin protects against Th17 cell‐mediated EAE independently of YAP inhibition. Eur. J. Immunol., 2022, Vol. 52, no. 9, pp. 1523-1526. DOI: 10.1002/eji.202149564

9. Cai X., Wang K. C., Meng Z. Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression. Front. Cell Dev. Biol., 2021, Vol. 9, 673599. DOI: 10.3389/fcell.2021.673599

10. Calvo V., Izquierdo M. Role of Actin Cytoskeleton Reorganization in Polarized Secretory Traffic at the Immunological Synapse. Front. Cell Dev. Biol., 2021, Vol. 9, 629097. DOI: 10.3389/fcell.2021.629097

11. Cheever A., Townsend M., O’Neill K. Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors Cells, 2022, Vol. 11, no, 22, 3626. DOI: 10.3390/cells11223626

12. Chen D.S. Immunity as biophysics at the surface of a T cell. Immunity, 2024, Vol. 57, no. 2, pp.193-195. DOI: 10.1016/j.immuni.2024.01.015

13. Coste, B., Mathur, J., Schmidt, M., Earley, T. J., Ranade, S., Petrus, M. J., Dubin, A. E., Patapoutian A. Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science, 2010, Vol. 330, no. 6000, pp. 55-60. DOI: 10.1126/science.1193270

14. de Jesus M., Settle A. H., Vorselen D., Gaetjens T. K., Galiano M., Wong Y. Y., Fu T. M., Santosa E., Winer B. Y., Tamzalit F., Wang M. S., Bao Z., Sun J. C., Shah P., Theriot J. A., Abel S. M., Huse M. Topographical analysis of immune cell interactions reveals a biomechanical signature for immune cytolysis, Biorxiv, 2023. DOI: 10.1101/2023.04.16.537078

15. De Marco R. C., Monzo H. J., Ojala P. M. CAR T Cell Therapy: A Versatile Living Drug. IJMS, 2023, Vol. 24, no. 7, 6300. DOI: 10.3390/ijms24076300

16. Douanne T., Griffiths G. M. Cytoskeletal control of the secretory immune synapse. Current Opinion in Cell Biology, 2021, Vol. 71, pp. 87-94. DOI: 10.1016/j.ceb.2021.02.008

17. Du, H., Bartleson, J. M., Butenko, S., Alonso, V., Liu, W. F., Winer, D. A., Butte, M. J. Tuning immunity through tissue mechanotransduction. Nat. Rev. Immunol., 2023, Vol. 23, no. 3, pp. 174-188. DOI: 10.1038/s41577-022-00761-w

18. Fang, X. Z., Zhou, T., Xu, J. Q., Wang, Y. X., Sun, M. M., He, Y. J., Pan, S. W., Xiong, W., Peng, Z. K., Gao, X. H., & Shang, Y. Structure, kinetic properties and biological function of mechanosensitive Piezo channels. Cell Biosci., 2021, Vol. 11, no. 1, p. 13. DOI: 10.1186/s13578-020-00522-z

19. Fu D., Xie D., Wang F., Chen B., Wang Z., Peng F. Mechanically Optimize T Cells Activation by Spiky Nanomotors. Front. Bioeng. Biotechnol., 2022, Vol. 10, 844091. DOI: 10.3389/fbioe.2022.844091

20. Ge H., Tian M., Pei Q., Tan F., Pei H. Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism. Front. Oncol., 2021, Vol. 11, 631991. DOI: 10.3389/fonc.2021.631991

21. Geng L., Zhang C., He C., Zhang K., Kan H., Mao A., Ma X. Physiological levels of fluid shear stress modulate vascular function through TRPV4 sparklets. ABBS, 2022, Vol. 54, no. 9, pp. 1268-1277. DOI: 10.3724/abbs.2022118

22. Geng X., Ho Y. C., Srinivasan R.S. Biochemical and mechanical signals in the lymphatic vasculature. Cell Mol. Life Sci., 2021, Vol. 78, no. 16, pp. 5903-5923. DOI: 10.1007/s00018-021-03886-8

23. Govendir M. A., Kempe D., Sianati S., Cremasco J., Mazalo J. K., Colakoglu F., Golo M., Poole K., Biro M. T cell cytoskeletal forces shape synapse topography for targeted lysis via membrane curvature bias of perforin. Developmental. Cell., 2022, Vol. 57, no. 18, pp. 2237-2247. DOI: 10.1016/j.devcel.2022.08.012

24. Graham K., Lienau P., Bader B., Prechtl S., Naujoks J., Lesche R., Weiske J., Kuehnlenz J., Brzezinka K., Potze L., Zanconato F., Nicke B., Montebaur A., Bone W., Golfier S., Kaulfuss S., Kopitz C., Pilari S., Steuber H., Hayat S., Kamburov A., Steffen A., Schlicker A., Buchgraber P., Braeuer N., Font N. A., Heinrich T., Kuhnke L., Nowak-Reppel K., Stresemann C., Steigemann P., Walter A. O., Blotta S., Ocker M., Lakner A., von Nussbaum F., Mumberg D., Eis K., Piccolo S., Lange M. Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling. Cell Chemical Biology, 2024, Vol. 31, no. 7, pp. 1247-1263. DOI: 10.1016/j.chembiol.2024.02.013

25. Gunzer M., Schäfer A., Borgmann S., Grabbe S., Zänker K. S., Bröcker E. B., Kämpgen E., Friedl P. Antigen Presentation in Extracellular Matrix: Interactions of T Cells with Dendritic Cells Are Dynamic, Short Lived, and Sequential. Immunity, 2000, Vol. 13, no. 3, pp. 323-332. DOI: 10.1016/S1074-7613(00)00032-7

26. Guo T., He C., Venado A., Zhou Y. Extracellular Matrix Stiffness in Lung Health and Disease. Compr. Physiol., 2022, Vol. 12, no. 3, pp. 3523-3558. DOI: 10.1002/cphy.c210032

27. Guo T., Wantono C., Tan Y., Deng F., Duan T., Liu D. Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease. Front. Physiol., 2023, Vol. 14, 1098129. DOI: 10.3389/fphys.2023.1098129

28. Eiring P., Vashist N., Wedekink F., Genssler S., Fischer B., Dahlhoff J., Mokhtari F., Kuzkina A., Welters M. J. P., Benz T. M., Sorger L., Thiemann V., Almanzar G., Selle M., Thein K., Späth J., Gonzalez M. C., Reitinger C., Ipsen-Escobedo A., Wistuba-Hamprecht K., Eichler K., Filipski K., Zeiner P. S., Beschorner R., Goedemans R., Gogolla F. H., Hackl H., Rooswinkel R. W., Thiem A., Roche P. R., Joshi H., Pühringer D., Wöckel A., Diessner J. E., Rüdiger M., Leo E., Cheng P. F., Levesque M. P., Goebeler M., Sauer M., Nimmerjahn F., Schuberth-Wagner C., von Felten S., Mittelbronn M., Mehling M., Beilhack A., van der Burg S. H., Riedel A., Weide B., Dummer R., Wischhusen J. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat. Commun., 2023, Vol. 14, no. 1, p. 4253. DOI: 10.1038/s41467-023-39817-3

29. Hagenbeek T. J., Zbieg J. R., Hafner M., Mroue R., Lacap J. A., Sodir N. M., Noland C. L., Afghani S., Kishore A., Bhat K. P., Yao X., Schmidt S., Clausen S., Steffek M., Lee W., Beroza P., Martin S., Lin E., Fong R., Di Lello P., Kubala M. H., Yang M. N., Lau J. T., Chan E., Arrazate A., An L., Levy E., Lorenzo M. N., Lee H. J., Pham T. H., Modrusan Z., Zang R., Chen Y. C., Kabza M., Ahmed M., Li J., Chang M. T., Maddalo D., Evangelista M., Ye X., Crawford J. J., Dey A. An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance. Nat. Cancer, 2023, Vol. 4, no. 6, pp. 812-828. DOI: 10.1038/s43018-023-00577-0

30. Hasegawa K., Fujii S., Matsumoto S., Tajiri Y., Kikuchi A., Kiyoshima T. YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation. The Journal of Pathology, 2021, Vol. 253, no. 1, pp. 80-93. DOI: 10.1002/path.5553

31. Hope J. M., Dombroski J. A., Pereles R. S., Lopez-Cavestany M., Greenlee J. D., Schwager S. C., Reinhart-King C. A., King M. R. Fluid shear stress enhances T cell activation through Piezo1. BMC Biol., 2022, Vol. 20, no. 1, p. 61. DOI: 10.1186/s12915-022-01266-7

32. Humphries J. D., Chastney M. R., Askari J. A., Humphries M. J. Signal transduction via integrin adhesion complexes. Current Opinion in Cell Biology, 2019, Vol. 56, pp. 14-21. DOI: 10.1016/j.ceb.2018.08.004

33. Huttenlocher A., Horwitz A. R. Integrins in Cell Migration. Cold Spring Harbor Perspectives in Biology, 2011, Vol. 3, no. 9, a005074-a005074. DOI: 10.1101/cshperspect.a005074

34. Hyun J., Kim S. J., Cho S. D., Kim H. W. Mechano-modulation of T cells for cancer immunotherapy. Biomaterials, 2023, Vol. 297, 122101. DOI: 10.1016/j.biomaterials.2023.122101

35. Jiang W., Wijerathne T. D., Zhang H., Lin Y. C., Jo S., Im W., Lacroix J. J., Luo Y. L. Structural and thermodynamic framework for PIEZO1 modulation by small molecules. Proc. Natl. Acad. Sci USA, 2023, Vol. 120, no. 50, e2310933120. DOI: 10.1073/pnas.2310933120

36. Jiang Y., Yang X., Jiang J., Xiao B. Structural Designs and Mechanogating Mechanisms of the Mechanosensitive Piezo Channels. Trends in Biochemical Sciences, 2021, Vol. 46, no. 6, pp. 472-488. DOI: 10.1016/j.tibs.2021.01.008

37. Jin W., Tamzalit F., Chaudhuri P. K., Black C. T., Huse M., Kam L. C. T cell activation and immune synapse organization respond to the microscale mechanics of structured surfaces. Proc. Natl. Acad. Sci. USA, 2019, Vol. 116, no. 40, pp. 19835-19840. DOI: 10.1073/pnas.1906986116

38. Jung P., Zhou X., Iden S., Bischoff M., Qu B. T cell stiffness is enhanced upon formation of immunological synapse. Elife, 2021, no. 10, e66643. DOI: 10.7554/eLife.66643

39. Kastan N., Gnedeva K., Alisch T., Petelski A. A., Huggins D. J., Chiaravalli J., Aharanov A., Shakked A., Tzahor E., Nagiel A., Segil N., Hudspeth A. J. Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues. Nat. Commun., 2021, Vol. 12, no. 1, p. 3100. DOI: 10.1038/s41467-021-23395-3

40. Kastan N. R., Oak S., Liang R., Baxt L., Myers R. W., Ginn J., Liverton N., Huggins D. J., Pichardo J., Paul M., Carroll T. S., Nagiel A., Gnedeva K., Hudspeth A. J. Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs. Proc. Natl. Acad. Sci. USA, 2022, Vol. 119, no. 28, e2206113119. DOI: 10.1073/pnas.2206113119

41. Kim T. J. Mechanobiology: A New Frontier in Biology. Biology, 2021, Vol. 10, no. 7, p. 570. DOI: 10.3390/biology10070570

42. Kinsella J. A., Debant M., Parsonage G., Morley L. C., Bajarwan M., Revill C., Foster R., Beech D. J. Pharmacology of PIEZO1 channels. British J Pharmacology., 2024m Vol. 181, no. 23, pp. 4714-4732. DOI: 10.1111/bph.17351

43. Kolasangiani R., Bidone T. C., Schwartz M. A. Integrin Conformational Dynamics and Mechanotransduction. Cells, 2022, Vol. 11, no. 22, 3584. DOI: 10.3390/cells11223584

44. Koo J. H., Guan K. L. Interplay between YAP/TAZ and Metabolism. Cell Metabolism, 2018, Vol. 28, no. 2, pp. 196-206. DOI: 10.1016/j.cmet.2018.07.010

45. Lämmermann T., Bader B. L., Monkley S. J., Worbs T., Wedlich-Söldner R., Hirsch K., Keller M., Förster R., Critchley D. R., Fässler R., Sixt M. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature, 2008, Vol. 453, no. 7191, pp. 51-55. DOI: 10.1038/nature06887

46. Lebid A., Chung L., Pardoll D. M., Pan F. YAP Attenuates CD8 T Cell-Mediated Anti-tumor Response. Front. Immunol., 2020, Vol. 11, p. 580. DOI: 10.3389/fimmu.2020.00580

47. Lei K., Kurum A., Kaynak M., Bonati L., Han Y., Cencen V., Gao M., Xie Y. Q., Guo Y., Hannebelle M. T. M., Wu Y., Zhou G., Guo M., Fantner G. E., Sakar M. S., Tang L., Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat. Biomed. Eng., 2021. Vol. 5, no. 12, pp. 1411-1425. DOI: 10.1038/s41551-021-00826-6

48. Liu B., Kolawole E. M., Evavold B. D. Mechanobiology of T Cell Activation: To Catch a Bond. Annu Rev. Cell Dev. Biol., 2021, Vol. 37, no. 1, pp. 65-87. DOI: 10.1146/annurev-cellbio-120219-055100

49. Liu C. S. C., Mandal T., Biswas P., Hoque M. A., Bandopadhyay P., Sinha B. P., Sarif J., D'Rozario R., Sinha D. K., Sinha B., Ganguly D. Piezo1 mechanosensing regulates integrin-dependent chemotactic migration in human T cells. eLife, 2024, Vol. 12, RP91903. DOI: 10.7554/eLife.91903

50. Liu S., Pan X., Cheng W., Deng B., He Y., Zhang L., Ning Y., Li J. Tubeimoside I Antagonizes Yoda1-Evoked Piezo1 Channel Activation. Front. Pharmacol., 2020, Vol. 11, p. 768. DOI: 10.3389/fphar.2020.00768

51. Luthold C., Hallal T., Labbé D. P., Bordeleau F. The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance? Cancers, 2022, Vol. 14, no, 12, 2887. DOI: 10.3390/cancers14122887

52. Lv D., Fei Y., Chen H., Wang J., Han W., Cui B., Feng Y., Zhang P., Chen J. Crosstalk between T lymphocyte and extracellular matrix in tumor microenvironment. Front. Immunol., 2024, Vol. 15, 1340702. DOI: 10.3389/fimmu.2024.1340702

53. Mancuso R. V., Schneider G., Hürzeler M., Gut M., Zurflüh J., Breitenstein W., Bouitbir J., Reisen F., Atz K., Ehrhardt C., Duthaler U., Gygax D., Schmidt A. G., Krähenbühl S., Weitz-Schmidt G. Allosteric targeting resolves limitations of earlier LFA-1 directed modalities. Biochemical Pharmacology, 2023, Vol. 211, 115504. DOI: 10.1016/j.bcp.2023.115504

54. Martino F., Perestrelo A. R., Vinarský V., Pagliari S., Forte G. Cellular Mechanotransduction: From Tension to Function. Front. Physiol, 2018, Vol. 9, p. 824. DOI: 10.3389/fphys.2018.00824

55. Meng K. P., Majedi F. S., Thauland T. J., Butte M. J. Mechanosensing through YAP controls T cell activation and metabolism. Journal of Experimental Medicine, 2020, Vol. 217, no. 8, e20200053. DOI: 10.1084/jem.20200053

56. Mierke C.T. Extracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells. Cells, 2024, Vol. 13, no. 1, p. 96. DOI: 10.3390/cells13010096

57. Montironi C., Muñoz-Pinedo C., Eldering E. Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions. Cancers, 2021, Vol. 13, no. 2, p. 284. DOI: 10.3390/cancers13020284

58. Murugesan S., Hong J., Yi J., Li D., Beach J. R., Shao L., Meinhardt J., Madison G., Wu X., Betzig E., Hammer J. A. Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse. Journal of Cell Biology, 2016, Vol. 215, no. 3, pp. 383-399. DOI: 10.1083/jcb.201603080

59. Narciso M., Martínez Á., Júnior C., Díaz-Valdivia N., Ulldemolins A., Berardi M., Neal K., Navajas D., Farré R., Alcaraz J., Almendros I., Gavara N. Lung Micrometastases Display ECM Depletion and Softening While Macrometastases Are 30-Fold Stiffer and Enriched in Fibronectin. Cancers, 2023, Vol. 15, no. 8, 2404. DOI: 10.3390/cancers15082404

60. Nelson C. M., Xiao B., Wickström S. A., Dufrêne Y. F., Cosgrove D. J., Heisenberg C. P., Dupont S., Shyer A. E., Rodrigues A. R., Trepat X., Diz-Muñoz A. Mechanobiology: Shaping the future of cellular form and function. Cell, 2024, Vol. 187, no. 11, pp. 2652-2656. DOI: 10.1016/j.cell.2024.04.006

61. Ni X., Tao J., Barbi J., Chen Q., Park B. V., Li Z., Zhang N., Lebid A., Ramaswamy A., Wei P., Zheng Y., Zhang X., Wu X., Vignali P., Yang C. P., Li H., Pardoll D., Lu L., Pan D., Pan F. YAP Is Essential for Treg-Mediated Suppression of Antitumor Immunity. Cancer Discovery, 2018, Vol. 8, no. 8, pp. 1026-1043. DOI: 10.1158/2159-8290.CD-17-1124

62. Nicolas N., De Tilly A., Roux E. Blood shear stress during the cardiac cycle and endothelial cell orientation and polarity in the carotid artery of male and female mice. Front. Physiol., 2024, Vol. 15, 1386151. DOI: 10.3389/fphys.2024.1386151

63. Pang R., Sun W., Yang Y., Wen D., Lin F., Wang D., Li K., Zhang N., Liang J., Xiong C., Liu Y. PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes. Nat. Biomed. Eng., 2024, Vol. 8, no. 9, pp. 1162-1176. DOI: 10.1038/s41551-024-01188-5

64. Pang X., He X., Qiu Z., Zhang H., Xie R., Liu Z., Gu Y., Zhao N., Xiang Q., Cui Y. Targeting integrin pathways: mechanisms and advances in therapy. Sig. Transduct. Target Ther., 2023, Vol. 8, no. 1, p. 1. DOI: 10.1038/s41392-022-01259-6

65. Pathni A., Özçelikkale A., Rey-Suarez I., Li L., Davis S., Rogers N., Xiao Z., Upadhyaya A. Cytotoxic T Lymphocyte Activation Signals Modulate Cytoskeletal Dynamics and Mechanical Force Generation. Front. Immunol., 2022, Vol. 13, 779888. DOI: 10.3389/fimmu.2022.779888

66. Pathni A., Wagh K., Rey-Suarez I., Upadhyaya A. Mechanical regulation of lymphocyte activation and function. Journal of Cell Science, 2024, Vol. 137, no. 13, jcs219030. DOI: 10.1242/jcs.219030

67. Pocaterra A., Romani P., Dupont S. YAP/TAZ functions and their regulation at a glance. Journal of Cell Science, 2020, Vol. 133, no. 2, jcs230425. DOI: 10.1242/jcs.230425

68. Pribila J. T., Quale A. C., Mueller K. L., Shimizu Y. Integrins and T Cell–Mediated Immunity. Annu Rev. Immunol. 2004, Vol. 22, no. 1, pp. 157-180. DOI: 10.1146/annurev.immunol.22.012703.104649

69. Reversat A., Gaertner F., Merrin J., Stopp J., Tasciyan S., Aguilera J., de Vries I., Hauschild R., Hons M., Piel M., Callan-Jones A., Voituriez R., Sixt M. Cellular locomotion using environmental topography. Nature, 2020, Vol. 582, no. 7813, pp. 582-585. DOI: 10.1038/s41586-020-2283-z

70. Rogers J., Bajur A. T., Salaita K., Spillane K. M. Mechanical control of antigen detection and discrimination by T and B cell receptors. Biophysical Journal, 2024, Vol. 123, no. 15, pp. 2234-2255. DOI: 10.1016/j.bpj.2024.05.020

71. Rømer A. M. A., Thorseth M. L., Madsen D. H. Immune Modulatory Properties of Collagen in Cancer. Front. Immunol., 2021, Vol. 12, 791453. DOI: 10.3389/fimmu.2021.791453

72. Roy N. H., Kim S. H. J., Buffone A. Jr., Blumenthal D., Huang B., Agarwal S., Schwartzberg P. L., Hammer D. A., Burkhardt J. K. LFA-1 signals to promote actin polymerization and upstream migration in T cells. J. Cell Sci., 2020, Vol. 133, no. 17, jcs248328. DOI: 10.1242/jcs.248328

73. Sapudom J., Alatoom A., Tipay P. S., Teo J. Cm. Matrix stiffening from collagen fibril density and alignment modulates YAP-mediated T-cell immune suppression. Biomaterials, 2025, Vol. 315, 122900. DOI: 10.1016/j.biomaterials.2024.122900

74. Sarna N. S., Desai S. H., Kaufman B. G., Curry N. M., Hanna A. M., King M. R. Enhanced and sustained T cell activation in response to fluid shear stress. iScience, 2024, Vol. 27, no. 6, 109999. DOI: 10.1016/j.isci.2024.109999

75. Schoppmeyer R., van Steen A. C. I., Kempers L., Timmerman A. L., Nolte M. A., Hombrink P., van Buul J.D. The endothelial diapedesis synapse regulates transcellular migration of human T lymphocytes in a CX3CL1- and SNAP23-dependent manner. Cell Reports, 2022, Vol. 38, no. 3, 110243. DOI: 10.1016/j.celrep.2021.110243

76. Secondino S., Canino C., Alaimo D., Muzzana M., Galli G., Borgetto S., Basso S., Bagnarino J., Pulvirenti C., Comoli P., Pedrazzoli P. Clinical Trials of Cellular Therapies in Solid Tumors. Cancers, 2023, Vol. 15, no. 14, 3667. DOI: 10.3390/cancers15143667

77. Seo J., Kim J. Regulation of Hippo signaling by actin remodeling. BMB Rep., 2018, Vol. 51, no. 3, pp. 151-156. DOI: 10.5483/BMBRep.2018.51.3.012

78. Shalhout S. Z., Yang P. Y., Grzelak E. M., Nutsch K., Shao S., Zambaldo C., Iaconelli J., Ibrahim L., Stanton C., Chadwick S. R., Chen E., DeRan M., Li S., Hull M., Wu X., Chatterjee A. K., Shen W., Camargo F. D., Schultz P. G., Bollong M. J. YAP-dependent proliferation by a small molecule targeting annexin A2. Nat. Chem. Biol., 2021, Vol. 17, no. 7, pp. 767-775. DOI: 10.1038/s41589-021-00755-0

79. Smith A., Stanley P., Jones K., Svensson L., McDowall A., Hogg N. The role of the integrin LFA‐1 in T‐lymphocyte migration. Immunological Reviews, 2007, Vol. 218, no. 1, pp. 135-146. DOI: 10.1111/j.1600-065X.2007.00537.x

80. Sturbaut M., Bailly F., Coevoet M., Sileo P., Pugniere M., Liberelle M., Magnez R., Thuru X., Chartier-Harlin M. C., Melnyk P., Gelin M., Allemand F., Guichou J. F., Cotelle P. Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors. European Journal of Medicinal Chemistry, 2021, Vol. 226, 113835. DOI: 10.1016/j.ejmech.2021.113835

81. Sun D., Shi X., Li S., Wang X., Yang X., Wan M. CAR‑T cell therapy: A breakthrough in traditional cancer treatment strategies (Review). Mol. Med. Rep., 2024, Vol. 29, no. 3, p. 47. DOI: 10.3892/mmr.2024.13171

82. Sundqvist K. G. T Cell Motility ─ How Is It Regulated? Front. Immunol., 2020, Vol. 11, 588642. DOI: 10.3389/fimmu.2020.588642

83. Tamzalit F., Wang M. S., Jin W., Tello-Lafoz M., Boyko V., Heddleston J. M., Black C. T., Kam L. C., Huse M. Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells. Sci Immunol., 2019, Vol. 4, no. 33, eaav5445. DOI: 10.1126/sciimmunol.aav5445

84. Tang H., Zeng R., He E., Zhang I., Ding C., Zhang A. Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1): A Promising Therapeutic Target and Its Modulators: Miniperspective. J. Med. Chem., 2022, Vol. 65, no. 9, pp. 6441-6453. DOI: 10.1021/acs.jmedchem.2c00085

85. Taylor E. B., Wolf V. L., Dent E., Ryan M. J. Mechanisms of hypertension in autoimmune rheumatic diseases. British J. Pharmacology, 2019, Vol. 176, no. 12, pp. 1897-1913. DOI: 10.1111/bph.14604

86. Thien N. D., Hai-Nam N., Anh D. T., Baecker D. Piezo1 and its inhibitors: Overview and perspectives. European Journal of Medicinal Chemistry, 2024, Vol. 273, 116502. DOI: 10.1016/j.ejmech.2024.116502

87. Walling B. L., Kim M. LFA-1 in T Cell Migration and Differentiation. Front. Immunol., 2018, Vol. 9, p. 952. DOI: 10.3389/fimmu.2018.00952

88. Wang H. J., Wang Y., Mirjavadi S. S., Andersen T., Moldovan L., Vatankhah P., Russell B., Jin J., Zhou Z., Li Q., Cox C. D., Su Q. P., Ju L. A. Microscale geometrical modulation of PIEZO1 mediated mechanosensing through cytoskeletal redistribution. Nat. Commun., 2024, Vol. 15, no. 1, 5521. DOI: 10.1038/s41467-024-49833-6

89. Wang M. S., Hu Y., Sanchez E. E., Xie X., Roy N. H., de Jesus M., Winer B. Y., Zale E. A., Jin W., Sachar C., Lee J. H., Hong Y., Kim M., Kam L. C., Salaita K., Huse M. Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity. Nat. Commun., 2022, Vol. 13, no. 1, p. 3222. DOI: 10.1038/s41467-022-30809-3

90. Wijerathne T. D., Ozkan A. D., Lacroix J. J. Yoda1’s energetic footprint on Piezo1 channels and its modulation by voltage and temperature. Proc. Natl. Acad. Sci USA, 2022, Vol. 119, no. 29, e2202269119. DOI: 10.1073/pnas.2202269119

91. Winkler J., Abisoye-Ogunniyan A., Metcalf K. J., Werb Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun., 2020, Vol. 11, no. 1, p. 5120. DOI: 10.1038/s41467-020-18794-x

92. Wong D. C. P., Ding J. L. The mechanobiology of NK cells – “Forcing NK to Sense” target cells. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 2023, Vol. 1878, no. 2, 188860. DOI: 10.1016/j.bbcan.2023.188860

93. Woolf E., Grigorova I., Sagiv A., Grabovsky V., Feigelson S. W., Shulman Z., Hartmann T., Sixt M., Cyster J. G., Alon R. Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nat. Immunol., 2007, Vol. 8, no. 10, pp. 1076-1085. DOI: 10.1038/ni1499

94. Wu J., Lewis A. H., Grandl J. Touch, Tension, and Transduction – The Function and Regulation of Piezo Ion Channels. Trends in Biochemical Sciences, 2017, Vol. 42, no. 1, pp. 57-71. DOI: 10.1016/j.tibs.2016.09.004

95. Xie D., Fu D., Fu S., Chen B., He W., Wilson D. A., Peng F. Mechanical Activation of Immune T Cells via a Water Driven Nanomotor. Adv. Healthcare Materials, 2022, Vol. 11, no. 12, 2200042. DOI: 10.1002/adhm.202200042

96. Yang C., Xie R., Cao T., Zhang Y., Xe Y., Fan Q., Wang X., Ye F. Mechanical communication and function regulation of immune cells. Fundamental Research, 2024, S2667325824001523. DOI: 10.1016/j.fmre.2024.04.008

97. Yang X., Lin C., Chen X., Li S., Li X., Xiao B. Structure deformation and curvature sensing of PIEZO1 in lipid membranes. Nature, 2022, Vol. 604, no. 7905, pp. 377-383. DOI: 10.1038/s41586-022-04574-8

98. Yong J., Li Y., Lin S., Wang Z., Xu Y. Inhibitors Targeting YAP in Gastric Cancer: Current Status and Future Perspectives. DDDT, 2021, Vol. 15, pp. 2445-2456. DOI: 10.2147/DDDT.S308377

99. Yuan D. J., Shi L., Kam L. C. Biphasic response of T cell activation to substrate stiffness. Biomaterials, 2021, Vol. 273, 120797. DOI: 10.1016/j.biomaterials.2021.120797

100. Zagiel B., Melnyk P., Cotelle P. Progress with YAP/TAZ-TEAD inhibitors: a patent review (2018-present). Expert Opinion on Therapeutic Patents, 2022, Vol. 32, no. 8, pp. 899-912. DOI: 10.1080/13543776.2022.2096436

101. Zhao B., Pobbati A. V., Rubin B. P., Stauffer S. Leveraging Hot Spots of TEAD–Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling. Pharmaceuticals, 2023, Vol. 16, no. 4, p. 583. DOI: 10.3390/ph16040583

102. Zhou Z., Martinac B. Mechanisms of PIEZO Channel Inactivation. IJMS, 2023, Vol. 24, no. 18, 14113. DOI: 10.3390/ijms241814113

103. Zhu B., Qian W., Han C., Bai T., Hou X. Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis. Molecular Therapy  Nucleic Acids, 2021, Vol. 24, pp. 241-252. DOI: 10.1016/j.omtn.2021.02.026

104. Zhuang C., Gould J. E., Enninful A., Shao S., Mak M. Biophysical and mechanobiological considerations for T-cell-based immunotherapy. Trends in Pharmacological Sciences, 2023, Vol. 44, no. 6, pp. 366-378. DOI: 10.1016/j.tips.2023.03.007

105. Zimmerman T., Blanco F. Inhibitors Targeting the LFA-1/ICAM-1 Cell-Adhesion Interaction: Design and Mechanism of Action. CPD, 2008, Vol. 14, no. 22, pp. 2128-2139. DOI: 10.2174/138161208785740225

106. Zuidema A., Wang W., Sonnenberg A. Crosstalk between Cell Adhesion Complexes in Regulation of Mechanotransduction. BioEssays, 2020, Vol. 42, no. 11, 2000119. DOI: 10.1002/bies.202000119