细胞刚度对肿瘤发生发展和免疫逃逸影响的研究进展

doi:10.19438/j.cjoms.2026.04.015

摘要/Abstract

摘要： 恶性肿瘤的进展与癌细胞软化密切相关。组织和细胞的刚度各不相同,肿瘤组织异质性强,其内部存在不同机械特性的克隆群体。刚度对肿瘤细胞增殖、转移和免疫逃逸等生物学行为存在重要影响。本文回顾刚度这一生物力学特征对肿瘤发生发展及治疗的影响,并探讨相关机制和潜在的靶向治疗策略。

关键词: 细胞刚度, 肿瘤微环境, 机械转导, 免疫逃逸

Abstract: The progression of malignant tumors is closely linked to mechanical softening of cancer cells. Tissues and cells vary in stiffness, and tumor tissues exhibit pronounced heterogeneity, comprising clonal populations with diverse mechanical properties. Stiffness significantly affects critical cellular behaviors such as proliferation, metastasis, and immune evasion in tumor cells. This review examined the influence of stiffness, a critical biomechanical feature, on tumor initiation, progression and therapeutic response, and explored the associated molecular mechanisms and potential targeting strategies.

Key words: Cellular stiffness, Tumor microenvironment, Mechanotransduction, Immune evasion

中图分类号:

R739.8

曾慧, 田国才, 徐骎, 张志愿. 细胞刚度对肿瘤发生发展和免疫逃逸影响的研究进展[J]. 中国口腔颌面外科杂志, 2026, 24(4): 413-420.

Zeng Hui, Tian Guocai, Xu Qin, Zhang Zhiyuan. The role of cellular stiffness in tumorigenesis, progression and immune evasion[J]. China J Oral Maxillofac Surg, 2026, 24(4): 413-420.

参考文献

[1] Bray F, Laversanne M, Sung H, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2] Calzado-Martín A, Encinar M, Tamayo J, et al.Effect of actin organization on the stiffness of living breast cancer cells revealed by peak-force modulation atomic force microscopy[J]. ACS Nano, 2016, 10(3): 3365-3374.
[3] Kalli M, Poskus MD, Stylianopoulos T, et al.Beyond matrix stiffness: targeting force-induced cancer drug resistance[J]. Trends Cancer, 2023, 9(11): 937-954.
[4] Park S, Jang WJ, Jeong CH.Nano-biomechanical validation of epithelial-mesenchymal transition in oral squamous cell carcinomas[J]. Biol Pharm Bull, 2016, 39(9): 1488-1495.
[5] Fuhs T, Wetzel F, Fritsch AW, et al.Rigid tumours contain soft cancer cells[J]. Nat Phys, 2022, 18(12): 1510-1519.
[6] Rianna C, Radmacher M, Kumar S.Direct evidence that tumor cells soften when navigating confined spaces[J]. Mol Biol Cell, 2020, 31(16): 1726-1734.
[7] Zhang Y, Fu Q, Sun W, et al.Mechanical forces in the tumor microenvironment: roles, pathways, and therapeutic approaches[J]. J Transl Med, 2025, 23(1): 313.
[8] Yang YA, Nguyen E, Sankara Narayana GHN, et al. Local contractions regulate E-cadherin rigidity sensing [J]. Sci Adv, 2022, 8(4): eabk0387.
[9] Hartmann B, Fleischhauer L, Nicolau M, et al.Profiling native pulmonary basement membrane stiffness using atomic force microscopy[J]. Nat Protoc, 2024, 19(5): 1498-1528.
[10] 衡扬, 闫加奇, 俞文强, 等. 细胞力学特性测量方法及应用[J]. 中国科学: 生命科学, 2023, 53(9): 1247-1273.
Heng Y, Yan JQ, Yu WQ, et al.Measurement methods and application of mechanical properties of cells[J]. Scientia Sinica(Vitae), 2023, 53(9): 1247-1273.
[11] Lekka M.Applicability of atomic force microscopy to determine cancer-related changes in cells[J]. Philos Trans A Math Phys Eng Sci, 2022, 380(2232): 20210346.
[12] Skverchinskaya E, Levdarovich N, Ivanov A, et al.Anticancer drugs paclitaxel, carboplatin, doxorubicin, and cyclophosphamide alter the biophysical characteristics of red blood cells, in vitro[J]. Biology (Basel), 2023, 12(2): 230.
[13] Jeffreys N, Brockman JM, Zhai Y, et al.Mechanical forces amplify TCR mechanotransduction in T cell activation and function[J]. Appl Phys Rev, 2024, 11(1): 011304.
[14] Si J, Wang C, Zhang D, et al.Osteopontin in bone metabolism and bone diseases[J]. Med Sci Monit, 2020, 26: e919159.
[15] Zhang B, Luo Q, Mao X, et al.A synthetic mechano-growth factor E peptide promotes rat tenocyte migration by lessening cell stiffness and increasing F-actin formation via the FAK-ERK1/2 signaling pathway[J]. Exp Cell Res, 2014, 322(1): 208-216.
[16] Harn HI, Wang YK, Hsu CK, et al.Mechanical coupling of cytoskeletal elasticity and force generation is crucial for understanding the migrating nature of keloid fibroblasts[J]. Exp Dermatol, 2015, 24(8): 579-584.
[17] Ghosh B, Nishida K, Chandrala L, et al. Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin [J]. J Cell Sci, 2022, 135(4): jcs258513.
[18] Lv J, Liu Y, Cheng F, et al.Cell softness regulates tumorigenicity and stemness of cancer cells[J]. EMBO J, 2021, 40(2): e106123.
[19] Swaminathan V, Mythreye K, O'Brien ET, et al. Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines[J]. Cancer Res, 2011, 71(15): 5075-5080.
[20] Han YL, Pegoraro AF, Li H, et al.Cell swelling, softening and invasion in a three-dimensional breast cancer model[J]. Nat Phys, 2020, 16(1): 101-108.
[21] Isert L, Passi M, Freystetter B, et al.Cellular EMT-status governs contact guidance in an electrospun TACS-mimicking in vitro model[J]. Mater Today Bio, 2025, 30: 101401.
[22] Chen YQ, Lan HY, Wu YC, et al.Epithelial-mesenchymal transition softens head and neck cancer cells to facilitate migration in 3D environments[J]. J Cell Mol Med, 2018, 22(8): 3837-3846.
[23] Kim DK, Kim EK, Jung DW, et al.Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts[J]. PLoS One, 2019, 14(3): e0214553.
[24] Zhang JY, Zhu WW, Wang MY, et al.Cancer-associated fibroblasts promote oral squamous cell carcinoma progression through LOX-mediated matrix stiffness[J]. J Transl Med, 2021, 19(1): 513.
[25] Benn MC, Pot SA, Moeller J, et al. How the mechanobiology orchestrates the iterative and reciprocal ECM-cell cross-talk that drives microtissue growth [J]. Sci Adv, 2023, 9(13): eadd9275.
[26] Li J, Xu J, Li L, et al.MGAT3-mediated glycosylation of tetraspanin CD82 at asparagine 157 suppresses ovarian cancer metastasis by inhibiting the integrin signaling pathway[J]. Theranostics, 2020, 10(14): 6467-6482.
[27] Torrino S, Grasset EM, Audebert S, et al. Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis [J]. Cell Metab, 2021, 33(7): 1342-1357.e10.
[28] Chastney MR, Kaivola J, Leppänen VM, et al.The role and regulation of integrins in cell migration and invasion[J]. Nat Rev Mol Cell Biol, 2025, 26(2): 147-167.
[29] Chien MH, Yang YC, Ho KH, et al.Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma[J]. Cell Death Dis, 2024, 15(1): 82.
[30] Kellett MD, Sharma V, Sherlock ME, et al.Focal adhesion kinase promotes ribosome biogenesis to drive advanced thyroid cancer cell growth and survival[J]. Front Oncol, 2025, 15: 1252544.
[31] Wang JY, Chen H, Dai SZ, et al.Immunotherapy combining tumor and endothelium cell lysis with immune enforcement by recombinant MIP-3α Newcastle disease virus in a vessel-targeting liposome enhances antitumor immunity[J]. J Immunother Cancer, 2022, 10(3): e004344.
[32] Orré T, Joly A, Karatas Z, et al.Molecular motion and tridimensional nanoscale localization of kindlin control integrin activation in focal adhesions[J]. Nat Commun, 2021, 12(1): 3104.
[33] Pernier J, Cardoso dos Santos M, Souissi M, et al. Talin and kindlin cooperate to control the density of integrin clusters [J]. J Cell Sci, 2023, 136(8): jcs260746.
[34] Lee JH, Son S, Ko Y, et al.Nidogen-1 suppresses cell proliferation, migration, and glycolysis via integrin β1-mediated HIF-1α downregulation in triple-negative breast cancer[J]. Sci Rep, 2025, 15(1): 10633.
[35] Zeng G, Shen Y, Sun W, et al.Phenotype remodelling of HNSCC cells in the muscle invasion environment[J]. J Transl Med, 2024, 22(1): 909.
[36] Wu Q, Chen P, Li J, et al.Inhibition of bladder cancer growth with homoharringtonine by inactivating integrin α5/β1-FAK/Src axis: a novel strategy for drug application[J]. Pharmacol Res, 2023, 188: 106654.
[37] Rice A, Cortes E, Lachowski D, et al.GPER activation inhibits cancer cell mechanotransduction and basement membrane invasion via RhoA[J]. Cancers (Basel), 2020, 12(2): 289.
[38] Terzi A, Maqoud F, Guido D, et al.Ion Channel-extracellular matrix interplay in colorectal cancer: a network-based approach to tumor microenvironment remodeling[J]. Int J Mol Sci, 2025, 26(11): 6189.
[39] Yu Y, Wu X, Liu S, et al.Piezo1 regulates migration and invasion of breast cancer cells via modulating cell mechanobiological properties[J]. Acta Biochim Biophys Sin (Shanghai), 2021, 53(1): 10-18.
[40] Arora C, Matic M, Bisceglia L, et al.The landscape of cancer-rewired GPCR signaling axes[J]. Cell Genom, 2024, 4(5): 100557.
[41] Hasegawa K, Fujii S, Matsumoto S, et al.YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation[J]. J Pathol, 2021, 253(1): 80-93.
[42] Liang X, Xu X, Wang F, et al.E-cadherin knockdown increases β-catenin reducing colorectal cancer chemosensitivity only in three-dimensional cultures[J]. Int J Oncol, 2015, 47(4): 1517-1527.
[43] Delgado-Bellido D, Zamudio-Martínez E, Fernández-Cortés M, et al.VE-cadherin modulates β-catenin/TCF-4 to enhance vasculogenic mimicry[J]. Cell Death Dis, 2023, 14(2): 135.
[44] Duong CN, Brückner R, Schmitt M, et al. Force-induced changes of α-catenin conformation stabilize vascular junctions independently of vinculin [J]. J Cell Sci, 2021, 134(24): jcs259012.
[45] Chow KH, Factor RE, Ullman KS.The nuclear envelope environment and its cancer connections[J]. Nat Rev Cancer, 2012, 12(3): 196-209.
[46] Nader GPF, Agüera-González S, Routet F, et al. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion [J]. Cell, 2021, 184(20): 5230-5246.e22.
[47] Jiao S, Li C, Guo F, et al.SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness[J]. Nat Commun, 2023, 14(1): 6416.
[48] Wang TC, Abolghasemzade S, McKee BP, et al. Matrix stiffness drives drop-like nuclear deformation and lamin A/C tension-dependent YAP nuclear localization[J]. Nat Commun, 2024, 15(1): 10151.
[49] Fischer T, Hayn A, Mierke CT.Effect of nuclear stiffness on cell mechanics and migration of human breast cancer cells[J]. Front Cell Dev Biol, 2020, 8: 393.
[50] Northcott JM, Dean IS, Mouw JK, et al.Feeling stress: the mechanics of cancer progression and aggression[J]. Front Cell Dev Biol, 2018, 6: 17.
[51] Bertero T, Oldham WM, Grasset EM, et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy[J]. Cell Metab, 2019, 29(1): 124-140.e10.
[52] Lei K, Kurum A, Kaynak M, et al.Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy[J]. Nat Biomed Eng, 2021, 5(12): 1411-1425.
[53] Zhang A, Miao K, Sun H, et al.Tumor heterogeneity reshapes the tumor microenvironment to influence drug resistance[J]. Int J Biol Sci, 2022, 18(7): 3019-3033.
[54] Darvishi B, Eisavand MR, Majidzadeh-A K, et al.Matrix stiffening and acquired resistance to chemotherapy: concepts and clinical significance[J]. Br J Cancer, 2022, 126(9): 1253-1263.
[55] Liang R, Song G.Matrix stiffness-driven cancer progression and the targeted therapeutic strategy[J]. Mechanobiol Med, 2023, 1(2): 100013.
[56] Wang Y, Jiang H, Su Z, et al.The drug resistance feature of acute myeloid leukemia is related to the cell stiffness[J]. Biophys Rev (Melville), 2025, 6(2): 021402.
[57] Moreira D, Sampath S, Won H, et al.Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity[J]. J Clin Invest, 2021, 131(2): e137001.
[58] Krupar R, Hautmann MG, Pathak RR, et al.Immunometabolic determinants of chemoradiotherapy response and survival in head and neck squamous cell carcinoma[J]. Am J Pathol, 2018, 188(1): 72-83.
[59] Zhang T, Jia Y, Yu Y, et al.Targeting the tumor biophysical microenvironment to reduce resistance to immunotherapy[J]. Adv Drug Deliv Rev, 2022, 186: 114319.
[60] Zhang Y, Li J, Guo X, et al.Tumor-specific MHC-II Activates CD4+ and CD8+ T cells in head and neck squamous cell carcinoma to boost immunotherapy efficacy[J]. Cancer Res, 2025, 85(17): 3258-3274.
[61] Balachandran VP, Beatty GL, Dougan SK.Broadening the impact of immunotherapy to pancreatic cancer: challenges and opportunities[J]. Gastroenterology, 2019, 156(7): 2056-2072.
[62] Bonner M, Askew D, Sathish Kumar V, et al.Piezo1 deletion enhances cross-priming of CD8+ T cells by tumor-infiltrating CD11b+ dendritic cells[J]. J Immunother Cancer, 2025, 13(6): e011815.
[63] Yanamandra AK, Zhang J, Montalvo G, et al.PIEZO1-mediated mechanosensing governs NK-cell killing efficiency and infiltration in three-dimensional matrices[J]. Eur J Immunol, 2024, 54(3): e2350693.
[64] Haage A, Schneider IC.Cellular contractility and extracellular matrix stiffness regulate matrix metalloproteinase activity in pancreatic cancer cells[J]. FASEB J, 2014, 28(8): 3589-3599.
[65] Fan X, Chen H, Li Y, et al.Actin-targeted magnetic nanomotors mechanically modulate the tumor mechanical microenvironment for cancer treatment[J]. ACS Nano, 2025, 19(6): 6454-6467.
[66] Su Y, Huang H, Luo T, et al.Cell-in-cell structure mediates in-cell killing suppressed by CD44[J]. Cell Discov, 2022, 8(1): 35.