Extracellular matrix stiffness: Mechanisms in tumor progression and therapeutic potential in cancer
Open accessAbstract
Tumor microenvironment (TME) is a complex ecosystem composed of both cellular and non-cellular components that surround tumor tissue. The extracellular matrix (ECM) is a key component of the TME, performing multiple essential functions by providing mechanical support, shaping the TME, regulating metabolism and signaling, and modulating immune responses, all of which profoundly influence cell behavior. The quantity and cross-linking status of stromal components are primary determinants of tissue stiffness. During tumor development, ECM stiffness not only serves as a barrier to hinder drug delivery but also promotes cancer progression by inducing mechanical stimulation that activates cell membrane receptors and mechanical sensors. Thus, a comprehensive understanding of how ECM stiffness regulates tumor progression is crucial for identifying potential therapeutic targets for cancer. This review examines the effects of ECM stiffness on tumor progression, encompassing proliferation, migration, metastasis, drug resistance, angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion, stemness, metabolic reprogramming, and genomic stability. Finally, we explore therapeutic strategies that target ECM stiffness and their implications for tumor progression.
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ECM stiffness triggers mechanotransduction pathways that influence tumor cell behavior, including activation of YAP/TAZ, FAK, and MAPK pathways and modulation of gene expression associated with proliferation, EMT, and drug resistance.
“However, beyond acting as a physical barrier, ECM stiffness also triggers mechanotransduction pathways that profoundly influence tumor cell behavior [91,92]. Mechanical cues generated by a stiffened matrix are sensed through integrin-based focal adhesions and transmitted via cytoskeletal tension to activate intracellular signaling cascades, including Yes-associated protein/Transcriptional coactiv”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [92]
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InfluentialYAP-mediated mechanotransduction tunes the macrophage inflammatory response
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Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure
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Mechanical stiffness controls dendritic cell metabolism and function
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Natural-Based Hydrogels for Tissue Engineering Applications
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Stiff matrix induces exosome secretion to promote tumour growth
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Targeting the Tumor Microenvironment in Cancer: Why Hyaluronidase Deserves a Second Look
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DNA repair defects in cancer and therapeutic opportunitiesPreprint
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Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors
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InfluentialTumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium
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Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis
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FAK in Cancer: From Mechanisms to Therapeutic Strategies
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Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma
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Revisiting the hallmarks of cancer: The role of hyaluronan
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Dual inhibition of TGF‐β and PD‐L1: a novel approach to cancer treatment
Gulley, J. L., Schlom, J., Barcellos‐Hoff, M. H., Wang, X., Seoane, J., Audhuy, F., Lan, Y., Dussault, I., & Moustakas, A. (2021) · Molecular Oncology · doi:10.1002/1878-0261.13146 · Cited by 178 · cited 1× · see citing works
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Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes
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“Quantitatively, this property is assessed using the elastic modulus [4].”
Basement membrane stiffness determines metastases formation
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“…LOX enhanced collagen cross-linking increases the stiffness of ECM, promotes the formation of focal adhesion, activates integrin β1, leads to increased phosphorylation of FAK/SRC and activation of PI3K signaling pathway, and ultimately promotes tumor cell invasion and tumor progression [38].”
Beyond matrix stiffness: targeting force-induced cancer drug resistance
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“Finally, TGFβ is also essential for inducing CSC phenotype [70], and by inhibiting the TGF-β pathway and down-regulating Id1 and Id3 expression, CD44high and Id1high GIC groups are reduced, thereby reducing the tumorigenic ability of GICs (Fig.”
InfluentialDummer, R., Ascierto, P. A., Basset‐Séguin, N., Dréno, B., Garbe, C., Gutzmer, R., Hauschild, A., Krattinger, R., Lear, J. T., Malvehy, J., et al. (2020) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.16230 · Cited by 169 · cited 1× · see citing works
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“The binding of E2F3 to the promoter of FGF2, confirmed by ChIP-qPCR, increases FGF2 expression, thereby promoting tumor proliferation and metastasis by activating FGFR1, PI3K/Akt, and MEK/ ERK signaling pathways in HCC cells [47].”
Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1
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“It has been reported to inhibit liver metastasis and improve survival in mouse models [138].”
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“In HCC cells, higher matrix stiffness significantly upregulates the expression of LOXL2 by activating the integrin β1/α5/JNK/c-JUN signaling pathway [27].”
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“Inhibiting FAK signaling may increase the susceptibility of PC9 gene resistance to EGFR-TKI in vitro and in vivo experiments [34].”
Cell Culture in Microfluidic Droplets
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“It mimics the ECM microenvironment in the body by precisely manipulating trace fluids through microfluidic devices, thus closer to the behavior of cells in the real physiological environment [203, 186–188].”
The regulation of immune cell trafficking by the extracellular matrix
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“Other immune cells, such as CD4 and CD8 T-cell blasts and monocyte lines, can also undergo protease and integrin β1 independent migration through type 1 collagen gels [80].”
Fibronectin-targeted drug delivery in cancer
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“Therefore, EDA and EDB domains have been widely utilized for the targeted delivery of therapeutic agents such as cytokines, cytotoxic drugs, chemotherapy drugs, and radioisotopes to tumors expressing FN, thus playing a significant therapeutic role in both primary cancer and metastatic lesions [123].”
Targeting the tumor microenvironment in B-cell lymphoma: challenges and opportunities
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“Mechanis-tically, MU consumed uridine diphosphate glucuronic acid, a precursor of ha, and reduced HAS mRNA expression; however, the inhibitory effect depended on the molecular weight of HA, because HMW-HA eliminated both inhibition and nonmetastasis of MU on MIA pCA-2 cells [1].”
The significant role of amino acid metabolic reprogramming in cancer
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“In macrophages, increased ECM stiffness results in reprogramming of arginine/pro-line metabolism and secretion of arginase, which impairs the antitumor activity of CD8 + T cells [103].”
Inhibition of fibronectin deposition improves experimental liver fibrosis
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“Furthermore, experimental data from in vitro studies on hepatic stellate cells indicate that pUR4, which inhibits FN assembly, reduces the deposition of FN and collagen in the extracellular matrix, with no influence on TGF-β or TNF-α [122].”
Synthetic hydrogels mimicking basement membrane matrices to promote cell-matrix interactions
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Characteristics of the cancer stem cell niche and therapeutic strategies
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“When cancer cells invade, they must be squeezed through narrower pores and undergo more physical damage [97].”
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“Normal healthy pancreas tissue has a stiffness of 1–3 kPa, whereas pancreatic carcinoma tissue has a stiffness of over 4 kPa [11, 12].”
Rath, N., Morton, J. P., Julian, L., Helbig, L., Kadir, S. R., McGhee, E. J., Anderson, K. I., Kalna, G., Mullin, M., Pinho, A. V., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606743 · Cited by 125 · see citing works
Decellularized Extracellular Matrix for Remodeling Bioengineering Organoid's Microenvironment
Zhu, L., Yuhan, J., Yu, H., Zhang, B., Huang, K., & Zhu, L. (2023) · Small · doi:10.1002/smll.202207752 · Cited by 123 · cited 2× · see citing works
“Despite all the advances in the field [202], the therapeutic application of decellularized ECM still faces challenges in terms of standardization and scaling, as well as ethical and regulatory constraints.”
The Role of Stromal Myofibroblast and Extracellular Matrix in Tumor Angiogenesis
Vong, S., & Kalluri, R. (2011) · Genes & Cancer · doi:10.1177/1947601911423940 · Cited by 122 · cited 2× · see citing works
“MMPs can degrade the matrix components, promote EC migration, and provide space for creating a new vascular sys-tem [68].”
Nuclear constriction segregates mobile nuclear proteins away from chromatin
Irianto, J., Pfeifer, C. R., Bennett, R. R., Xia, Y., Ivanovska, I. L., Liu, A. J., Greenberg, R. A., & Discher, D. E. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-06-0428 · Cited by 122 · cited 1× · see citing works
“This extrusion motion would allow some mobile proteins to be separated from DNA205 [106].”
Leveling Up Hydrogels: Hybrid Systems in Tissue Engineering
Neves, S. C., Moroni, L., Barrias, C. C., & Granja, P. L. (2019) · Trends in biotechnology · doi:10.1016/j.tibtech.2019.09.004 · Cited by 119 · cited 1× · see citing works
“…with the continuous development of the field of biomaterials, new engineered materials with independently adjustable BM-like bioactivity and mechanical properties have been developed [199], including Synthetic hydrogels, Decellu-larized ECM, Microfluidic cell culture, and 3D bioprinting [200].”
Aguilera, K. Y., Huang, H., Du, W., Hagopian, M. M., Wang, Z., Hinz, S., Hwang, T. H., Wang, H., Fleming, J. B., Castrillon, D. H., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0834 · Cited by 118 · cited 1× · see citing works
“Aguilera et al. demonstrated that pharmacological inhibition of DDR1 using an ATP-competitive, orally bioavailable small-molecule kinase inhibitor reduced colony formation and migration of pancreatic tumor cells [192].”
Chaudhry, G.-E.-S., Akim, A. M., Zafar, M. N., Safdar, N., Sung, Y. Y., & Muhammad, T. S. T. (2020) · Advanced Pharmaceutical Bulletin · doi:10.34172/apb.2021.050 · Cited by 117 · see citing works
Jeitany, M., Leroy, C., Tosti, P., Lafitte, M., Guet, J. L., Simon, V., Bonenfant, D., Robert, B., Grillet, F., Mollévi, C., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201707918 · Cited by 114 · see citing works
Setargew, Y. F. I., Wyllie, K., Grant, R. D., Chitty, J. L., & Cox, T. R. (2021) · Cancers · doi:10.3390/cancers13030491 · Cited by 114 · see citing works
Regulation of PD-L1 expression by matrix stiffness in lung cancer cells
Miyazawa, A., Ito, S., Asano, S., Tanaka, I., Sato, M., Kondo, M., & Hasegawa, Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.12.115 · Cited by 113 · see citing works
Positive and negative influence of the matrix architecture on antitumor immune surveillance
Peranzoni, E., Rivas-Caicedo, A., Bougherara, H., Salmon, H., & Donnadieu, E. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1339-8 · Cited by 108 · cited 1× · see citing works
“Collagen cross-linking is almost exclusively mediated by LOX [24], a copper-dependent, secreted amino oxidase encoded by the PLOD family.”
TRPV 4 regulates matrix stiffness and TGF β1‐induced epithelial‐mesenchymal transition
Sharma, S., Goswami, R., Zhang, D. X., & Rahaman, S. O. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13972 · Cited by 108 · cited 1× · see citing works
“TRPV4, as a mechanosensitive channel [62], is important for YAP/ TAZ nuclear translocation and activation of AKT, which are key steps in EMT induced by matrix stiffness and TGFβ1.”
Identification and Characterization of a Novel Integrin-Linked Kinase Inhibitor
Lee, S.-L., Hsu, E., Chou, C.-C., Chuang, H.-C., Bai, L., Kulp, S. K., & Chen, C. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm2007744 · Cited by 107 · see citing works
Modification of Extracellular Matrix Enhances Oncolytic Adenovirus Immunotherapy in Glioblastoma
Kiyokawa, J., Kawamura, Y., Ghouse, S. M., Acar, S., Barçın, E., Martínez‐Quintanilla, J., Martuza, R. L., Alemany, R., Rabkin, S. D., Shah, K., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2400 · Cited by 106 · cited 2× · see citing works
“Increased matrix stiffness enhances PD-L1 expression in cancer cells [81], which was associated with nuclear translocation of YAP/TAZ.”
LOXL2 Inhibitors and Breast Cancer Progression
Ferreira, S., Saraiva, N., Rijo, P. M., & Fernandes, A. S. (2021) · Antioxidants · doi:10.3390/antiox10020312 · Cited by 101 · cited 3× · see citing works
“These enzymes are found in a wide range of tissues and organs, such as aorta, heart, lung, and brain [26].”
InfluentialWang, T., Hamilla, S. M., Cam, M. C., Aranda‐Espinoza, H., & Mili, S. (2017) · Nature Communications · doi:10.1038/s41467-017-00884-y · Cited by 99 · cited 2× · see citing works
“3) [35].”
Ishihara, S., Inman, D. R., Li, W., Ponik, S. M., & Keely, P. J. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0569 · Cited by 96 · cited 1× · see citing works
“In addition, the increase of ECM stiffness in the TME can also induce MSC to differentiate into CAF and secrete the signaling protein prosaposin to realize the transduction of mechanical signals in MSCs, thereby triggering the proliferation and survival ability of cancer cells [94].”
Stiff substrates increase YAP-signaling-mediated matrix metalloproteinase-7 expression
Nukuda, A., Sasaki, C., Ishihara, S., Mizutani, T., Nakamura, K., Ayabe, T., Kawabata, K., & Haga, H. (2015) · Oncogenesis · doi:10.1038/oncsis.2015.24 · Cited by 95 · see citing works
Yang, N., Chen, T., Wang, L., Liu, R., Niu, Y., Sun, L., Yao, B., Wang, Y., Yang, W., Liu, Q., et al. (2020) · Theranostics · doi:10.7150/thno.44789 · Cited by 94 · cited 1× · see citing works
“In addition, UBTD1 plays a role in the proteasome-depend-ent degradation of YAP by facilitating its interaction with the E3 ubiquitin ligase β-TrCP [61].”
Zhou, X., Chen, N., Xu, H., Zhou, X., Wang, J., Fang, X., Zhang, Y., Li, Y., Yang, J., & Wang, X. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00906-1 · Cited by 94 · cited 2× · see citing works
“In addition, utilizing the CRISPR/Cas9 gene editing system to knock down YAP expression can hinder the proliferation of diffuse large B-cell lymphoma cells and trigger cell cycle arrest [65] (Tables 1 and 2).”
YAP/TAZ: Molecular pathway and disease therapy
Wei, Y., Hui, V. L. Z., Chen, Y., Han, R., Han, X., & Guo, Y. (2023) · MedComm · doi:10.1002/mco2.340 · Cited by 93 · cited 1× · see citing works
“Moreover, currently, most drugs in YAP/TAZ clinical trials target the combination of YAP/TAZ and TEAD, and all are in Phase I or II in solid tumor clinical trials [152].”
Cho, B. C., Daste, A., Ravaud, A., Salas, S., Isambert, N., McClay, E. F., Awada, A. H., Borel, C., Ojalvo, L. S., Helwig, C., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000664 · Cited by 92 · see citing works
Shinto, O., Yashiro, M., Kawajiri, H., Shimizu, K., Shimizu, T., Miwa, A., & Hirakawa, K. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605561 · Cited by 90 · cited 2× · see citing works
“Its mechanism of action is to activate cannabinoid receptor 2, leading to the production of prostaglandins, which reduce inflammatory cytokines and fibrosis [109].”
Integrins regulate stemness in solid tumor: an emerging therapeutic target
Xiong, J., Yan, L., Zou, C., Wang, K., Chen, M., Xu, B., Zhou, Z., & Zhang, D. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01192-1 · Cited by 89 · cited 2× · see citing works
“Integrins process biochemical and mechanical signals between cells and their environment in a variety of health and disease states [90].”
Laminins and cancer stem cells: Partners in crime?
Qin, Y., Rodin, S., Simonson, O. E., & Hollande, F. (2016) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2016.07.004 · Cited by 87 · cited 1× · see citing works
“For example, specific laminin isoforms such as laminin-111 play a key role in promoting stem cell differentiation and exit from pluripotency, as demonstrated by in vivo and in vitro experiments [98].”
Taufalele, P., Wang, W., Simmons, A. J., Southard-Smith, A. N., Chen, B., Greenlee, J. D., King, M. R., Lau, K. S., Hassane, D. C., Bordeleau, F., et al. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.04.031 · Cited by 87 · cited 1× · see citing works
“ECM stiffness not only acts as a physical barrier to hinder the infiltration of immune cells into the TME but also promotes the survival and proliferation of tumor cells by activating specific signaling pathways [85].”
Collagen cross-linking mediated by lysyl hydroxylase 2: an enzymatic battlefield to combat fibrosis
Piersma, B., & Bank, R. A. (2019) · Essays in Biochemistry · doi:10.1042/ebc20180051 · Cited by 85 · cited 1× · see citing works
“In addition to the excessive accumulation of collagen leading to fibrosis, another significant alteration is the increased cross-linking, which affects the stability of the collagen network and leads to irreversible fibrosis [111].”
Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells
Fan, Y., Sun, Q., Li, X., Feng, J., Ao, Z., Li, X., & Wang, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.718834 · Cited by 82 · cited 2× · see citing works
“Finally, although higher matrix stiffness did not alter YAP expression levels, it led to decreased phosphorylated YAP, facilitated its nuclear localization [31], and influenced gene expression [32].”
Biphasic response of T cell activation to substrate stiffness
Yuan, D. J., Shi, L., & Kam, L. C. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.120797 · Cited by 80 · cited 2× · see citing works
“…high ECM stiffness promotes glycolysis (Warburg effect), thereby stimulating lactate overproduction and exacerbates acidosis and hypoxia microenvironment by activating the integrin-FAK-YAP pathway, while higher ECM stiffness can regulate the metabolic function of T cells through hypoxia [84].”
Liu, D., Zhou, J., Wang, Y., Li, M., Jiang, H., Liu, Y., Yin, X., Ge, M., Xiang, X., Ying, J., et al. (2022) · BMC Medicine · doi:10.1186/s12916-022-02605-9 · Cited by 79 · cited 1× · see citing works
“…fusion protein incorporating the soluble ectodomain of TβRII has been shown to reduce the incidence of mammary tumor metastasis in transgenic mice [179] sTβRII-Fc When coupled with an oncolytic adenovirus, it inhibits TGF-β signaling and reduces tumor growth in vitro and nude mouse models [110]…”
Kurenova, E., Hunt, D. L., He, D.-H., Magis, A. T., Ostrov, D. A., & Cance, W. G. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900159g · Cited by 78 · cited 1× · see citing works
“Chloropyramine hydrochloride inhibits the proliferation and growth of cancer cells by inhibiting VEGFR-3 and FAK signaling [149].”
Redman, J. M., Friedman, J., Robbins, Y. L., Sievers, C. M., Yang, X., Lassoued, W., Sinkoe, A. L., Papanicolau‐Sengos, A., Lee, C. R., Marté, J. L., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci161400 · Cited by 77 · see citing works
Tumor matrix stiffness provides fertile soil for cancer stem cells
Safaei, S., Sajed, R., Shariftabrizi, A., Dorafshan, S., Zanjani, L. S., Manshadi, M. D., Madjd, Z., & Ghods, R. (2023) · Cancer Cell International · doi:10.1186/s12935-023-02992-w · Cited by 77 · cited 3× · see citing works
“However, this treatment should be considered with caution and is best applied in early-detected cancer cases with significant matrix stiffness and no signs of invasion or metastasis [91].”
Tanaka, H. (2010) · Oncology Reports · doi:10.3892/or_00001028 · Cited by 76 · cited 1× · see citing works
“…and second-line treatments, respectively TGF-βRI tyrosine kinase inhibitor SB-431542 A TβRI inhibitor developed by GlaxoSmithKline that blocks TGF-β-induced FN and collagen transcription in vitro [182] LY364947 A pyrazole-based compound that inhibits the serine-threonine kinase activity of TGF-βR1.”
The Interplay of the Extracellular Matrix and Stromal Cells as a Drug Target in Stroma-Rich Cancers
Kozlova, N., Grossman, J. E., Iwanicki, M. P., & Muranen, T. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.01.001 · Cited by 73 · cited 10× · see citing works
“Unfortunately, prinomastat failed in Phase III trials owing to its ineffectiveness in patients with advanced disease [21].”
InfluentialDiscoidin domain receptors orchestrate cancer progression: A focus on cancer therapies
Gao, Y., Zhou, J., & Li, J. (2020) · Cancer Science · doi:10.1111/cas.14789 · Cited by 73 · cited 2× · see citing works
“DDR1 is broadly expressed in epithelial cells, whereas DDR2 is predominantly found in mesenchymal cells [185].”
Nanocomposite Bioprinting for Tissue Engineering Applications
Loukelis, K., Helal, Z. A., Mikos, A. G., & Chatzinikolaidou, Μ. (2023) · Gels · doi:10.3390/gels9020103 · Cited by 72 · cited 1× · see citing works
“Finally, 3D bioprinting is a promising innovative biomanufacturing strategy for precisely locating biologics [204], including living cells and ECM components [189], in prescribed 3D hierarchical tissues to create artificial multicellular tissues/organs [205].”
Lu, Y., Jin, Z., Hou, J., Wu, X., Yu, Z., Yao, L., Pan, T., Chang, X., Yu, B., Li, J., et al. (2022) · Matrix Biology · doi:10.1016/j.matbio.2022.11.005 · Cited by 68 · see citing works
Hammer, A. M., Sizemore, G. M., Shukla, V. C., Avendano, A., Sizemore, S. T., Chang, J. J., Kladney, R. D., Cuitiño, M. C., Thies, K., Verfurth, Q., et al. (2017) · Neoplasia · doi:10.1016/j.neo.2017.04.004 · Cited by 64 · cited 1× · see citing works
“…interstitium, activated PDGFRα causes increased HA and collagen deposition in breast fibroblasts, inducing fibrosis of the mammary fat pad, and it is observed that fibrosis of the mammary gland significantly increases the overall stiffness of the breast as measured by atomic force microscopy [22].”
Chirivì, M., Maiullari, F., Milan, M., Presutti, D., Cordiglieri, C., Crosti, M., Sarnicola, M. L., Soluri, A., Volpi, M., Święszkowski, W., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115862 · Cited by 64 · cited 1× · see citing works
“…the tumor side, they have developed mechanisms to evade the action of the immune system, ranging from direct secretion of biochemical signals to indirect responses, in which the cellular participants of the TME cooperate to mechanically regulate the ECM to make it unsuitable for immune cells [77].”
Tamiello, C. C., Kamps, M. A. F., van den Wijngaard, A., Verstraeten, V. L. R. M., Baaijens, F. F., Broers, J. L. V., & Bouten, C. V. C. (2013) · Nucleus · doi:10.4161/nucl.23388 · Cited by 63 · cited 1× · see citing works
“Furthermore, matrix stiffness increases the probability of nuclear envelope breakdown [107], which allows nuclear contents such as nucleic acids and nucleases to leak into the cytoplasm, eventually causing DNA damage and genome integrity.”
Na, J., Tai, C., Wang, Z., Yang, Z., Chen, X., Zhang, J., Zheng, L., & Fan, Y. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122715 · Cited by 63 · cited 2× · see citing works
“For example, the ability of T cells to mount an antitumor response depends on the balance of a network of reticular fibers that promote migration against regions of unfavorable migration composed of dense and ordered ECM structures [15].”
Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer
Drain, A., Zahir, N., Northey, J. J., Zhang, H., Huang, P.-J., Maller, O., Lakins, J., Yu, X.-M., Leight, J., Alston-Mills, B., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20191360 · Cited by 62 · cited 1× · see citing works
“In addition, β1-integrin and FAK are also involved in the stiffness-dependent regulation of HCC cell proliferation [30].”
Gao, X., Qiao, X., Xing, X., Huang, J., Qian, J., Wang, Y., Zhang, Y., Zhang, X., Li, M., Cui, J., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01563 · Cited by 61 · see citing works
Feasibility of magnetic resonance elastography for the pancreas at 3T
Itoh, Y., Takehara, Y., 川瀬俊浩, Terashima, K., Ohkawa, Y., Hirose, Y., Koda, A., Hyodo, N., Ushio, T., Hirai, Y., et al. (2015) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.24995 · Cited by 59 · cited 1× · see citing works
“Normal healthy pancreas tissue has a stiffness of 1–3 kPa, whereas pancreatic carcinoma tissue has a stiffness of over 4 kPa [11, 12].”
A Soft Matrix Enhances the Cancer Stem Cell Phenotype of HCC Cells
Tian, B., Luo, Q., Ju, Y., & Song, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112831 · Cited by 59 · cited 4× · see citing works
“The soft matrix induces early G1 phase arrest of the cell cycle and enhances the ability of spheroid formation [33].”
InfluentialBao, M., Chen, Y., Liu, J.-T., Bao, H., Wang, W.-B., Qi, Y.-X., & Lv, F. (2021) · Angiogenesis · doi:10.1007/s10456-021-09804-7 · Cited by 59 · cited 2× · see citing works
“Thus, angiogenesis is promoted [66].”
Liu, X., Lu, Y., Huang, J., Xing, Y., Dai, H., Zhu, L., Li, S., Feng, J., Zhou, B., Li, J., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.10.015 · Cited by 59 · see citing works
Huo, Y., Yang, M., Liu, W., Yang, J., Fu, X., Liu, D., Li, J., Zhang, J., Hua, R., & Sun, Y. (2015) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-015-0202-1 · Cited by 56 · cited 1× · see citing works
“Emerging studies have demonstrated that DDR1 is a key regulator of cancer genesis, differentiation, migration, and invasion [191].”
The role of matrix stiffness in cancer stromal cell fate and targeting therapeutic strategies
Wei, J., Yao, J., Yan, M., Xie, Y., Liu, P., Mao, Y., & Li, X. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.08.005 · Cited by 56 · cited 3× · see citing works
“For example, during palatal healing, periostin increases ECM stiffness through FN synthesis and the integrin-β1/RhoA pathway, thereby affecting fibroblast differentiation and contraction [17–19].”
Multifaceted collagen-DDR1 signaling in cancer
Su, H., & Karin, M. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.08.003 · Cited by 55 · cited 3× · see citing works
“Inhibitors of the Wnt/β-catenin pathway (such as the tankyrase inhibitor XAV939) [155], inhibitors of Rho-GTPases and ROCK (such as fasudil) [156], and modulators of the SREBP/ mevalonate pathway (e.g., statins or bisphosphonates) can all attenuate YAP/TAZ activity [157].”
Anlaş, A. A., & Nelson, C. M. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-4021 · Cited by 48 · cited 1× · see citing works
“4b) [76].”
Wei, J., Yao, J., Yang, C., Mao, Y., Zhu, D., Xie, Y., Liu, P., Yan, M., Ren, L., Lin, Y., et al. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03778-w · Cited by 47 · cited 3× · see citing works
“However, in some cases, lower stiffness can also promote the proliferation of cancer cells by inducing the expression of the proliferation-related protein Ki67 [32], which has important implications for tumor treatment strategies (Fig.”
Chuang, Y.-C., Chang, H.-M., Li, C., Cui, Y., Lee, C.-L., & Chen, C. (2020) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.0c16638 · Cited by 46 · see citing works
Tan, B. R., Khattak, A., Felip, E., Kelly, K. L., Rich, P., Wang, D., Helwig, C., Dussault, I., Ojalvo, L. S., & Isambert, N. (2021) · Targeted Oncology · doi:10.1007/s11523-021-00809-2 · Cited by 46 · cited 1× · see citing works
“Findings suggested encouraging clinical efficacy in advanced solid tumors [176], and did not report any dose-limiting toxicity [177] SHR-1701 Developed by Henrui Pharma [165], Studies demonstrated no dose-limiting toxicity, and the maximum tolerated dose was not reached [178] Tβrii-fc A recombinant…”
Advances of targeting the YAP/TAZ-TEAD complex in the hippo pathway for the treatment of cancers
Luo, M., Xu, Y., Chen, H., Wu, Y., Pang, A., Hu, J., Dong, X., Che, J., & Yang, H. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114847 · Cited by 46 · cited 1× · see citing works
“Their activation positively correlates with malignancy, recurrence, metastasis, reduced overall survival, and drug resistance [150].”
Kang, Y., Bang, Y., Kondo, S., Chung, H. C., Muro, K., Dussault, I., Helwig, C., Osada, M., & Doi, T. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3806 · Cited by 44 · cited 1× · see citing works
“…of solid tumors and myelofibrosis Fusion Proteins Bintrafuspα A pioneering dual-function fusion protein that targets both PD-L1 and TGF-β [174, 175] has undergone evaluation in several Phase 2 trials for biliary tract cancer, non-small cell lung cancer, cervical cancer, and other solid tumors.”
Tomé, S., & Gourdon, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020457 · Cited by 43 · cited 1× · see citing works
“…b o d y b i n d i n g c y t o t o x i c d r u g t h a t h a s s h o w n p r o m i s - i n g r e s u l t s i n e x p e r i m e n t a l m o d e l s [ 160 ] S o n i d e g i b H h s i g n a l i n g p a t h w a y i nh i b i t o r , c o m b i n e d w i t h d o c e t a x e l i n p a t i e n t s w i t h…”
Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells
Martín-Otal, C., Lasarte-Cía, A., Serrano, D., Casares, N., Conde, E., Navarro, F. C., Sánchez-Moreno, I., Gorraiz, M., Sarrión, P., Calvo, A., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004479 · Cited by 42 · cited 2× · see citing works
“D-penicillamine has been used to treat diseases with collagen accumulation, such as liver fibrosis and progressive systemic sclerosis [116].”
Li, S., Bai, H., Chen, X., Gong, S., Xiao, J., Li, D., Li, L., Jiang, Y., Li, T., Qin, X., et al. (2020) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.0c00816 · Cited by 39 · cited 1× · see citing works
“…miR-29 significantly down-regulated and activated PI3K/Akt and Stat3 signaling pathways, and the expression of stemness-related transcription factors and sphere formation ability of osteosarcoma cells were enhanced, while the expansion area, proliferation, and migration were inhibited [96].”
Yang, L., Li, J., Zang, G., Song, S., Sun, Z., Li, X., Li, Y., Xie, Z., Zhang, G., Gui, N., et al. (2022) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10375 · Cited by 39 · cited 1× · see citing works
“In addition to the above mechanisms, matrix stiffness also regulates PPIase non-mitotic alpha interaction 1 -dependent YAP activity through a non-Hippo mechanism and positively regulates the EMT process [60].”
Tolcher, A. W., Gordon, M. S., Mahoney, K. M., Seto, A., Zavodovskaya, M., Hsueh, C., Zhai, S., Tarnowski, T. L., Jürgensmeier, J. M., Stinson, S., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005267 · Cited by 36 · cited 1× · see citing works
“…Dalutrafusp A bifunctional monoclonal antibody designed to target both CD73 and TGF-β, two key molecules involved in immunosuppressive pathways [180] Antisense Oligonucleotides AP12009 (Trabedersen) A phosphorothioate antisense oligonucleotide specifically targeting TGF-β2, which inhibits…”
Zhang, X., Al-Danakh, A. Y., Zhu, X., Feng, D., Yang, L., Wu, H., Li, Y., Wang, S., Chen, Q., & Yang, D. (2024) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10698 · Cited by 36 · cited 3× · see citing works
“Firstly, ECM stiffness leads to higher expression of critical glycolytic enzymes such as phosphofructokinase (PFK) and lactate dehydrogenase (LDH) by activating the YAP/TAZ signaling pathway [102].”
Biophysics Role and Biomimetic Culture Systems of ECM Stiffness in Cancer EMT
Tian, H., Shi, H., Yu, J., Ge, S., & Ruan, J. (2022) · Global Challenges · doi:10.1002/gch2.202100094 · Cited by 35 · cited 3× · see citing works
“One of the most fundamental biological processes in tumor metastasis is the EMT process [52].”
InfluentialKim, D., Ko, P., You, E., & Rhee, S. (2014) · International Journal of Cancer · doi:10.1002/ijc.28901 · Cited by 34 · cited 1× · see citing works
“Owing to the structural similarity of the KD, several putative tyrosine kinase inhibitors [157], such as dasatinib, salatinib, bosutinib, imatinib, and nilotinib [193], effectively block the kinase activity of either DDR1 or DDR2 [194].”
Extracellular matrix regulation of cell spheroid invasion in a 3D bioprinted solid tumor-on-a-chip
Dogan, E., Galifi, C. A., Çeçen, B., Shukla, R., Wood, T. L., & Miri, A. K. (2024) · Acta Biomaterialia · doi:10.1016/j.actbio.2024.07.040 · Cited by 33 · cited 2× · see citing works
“While high ECM stiffness promotes stem cell properties and increases cell proliferation in most cases [95], soft environments induce cell quiescence and enhance the expression of stem cell markers in HCC, including CD44, CD133, c-kit, CXCR4, OCT4, and NANOG [29].”
Zhang, L., Wang, Y., Xia, T., Yu, Q., Zhang, Q., Yang, Y., Cun, X., Lu, L., Gao, H., Zhang, Z., et al. (2016) · Drug Delivery · doi:10.3109/10717544.2015.1132798 · Cited by 32 · cited 2× · see citing works
“…y p r e - i n j e c - t i o n o f l o s a r t a n - e n c a p s u l a t e d l i p o s o m e s , a n d e nh a n c e s t h e a cc u - m u l a t i o n a n d p e n e t r a t i o n o f s u b s e q u e n t d e l i v e r y n a n o c a p s u l e s i n t h e t u m o r [ 113 ] barrier effect on tumor cells.”
DDR1-targeted therapies: current limitations and future potential
Wu, D., Ding, Z., Lu, T., Chen, Y., Zhang, F., & Lü, S. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.103975 · Cited by 32 · cited 1× · see citing works
“The molecular structure of DDR comprises three main parts: the extracellular binding domain, the transmembrane TM domain, and the intra-cellular kinase domain (KD) [184].”
Nanomedicine Strategies for Targeting Tumor Stroma
Su, M., Nethi, S. K., Dhanyamraju, P. K., & Prabha, S. (2023) · Cancers · doi:10.3390/cancers15164145 · Cited by 30 · see citing works
Kuermanbayi, S., Yang, Y., Zhao, Y., Li, Y., Wang, L., Yang, J., Zhou, Y., Xu, F., & Li, F. (2022) · Chemical Science · doi:10.1039/d2sc02708a · Cited by 28 · cited 1× · see citing works
“In addition, matrix stiffness can actively expel chemotherapy drugs from cancer cells by enhancing the functional activity of multidrug resistance protein 1 (MRP1) on the cell membrane, thus making cancer cells resistant to chemotherapy [72].”
Micalet, A., Pape, J., Bakkalci, D., Javanmardi, Y., Hall, C. M., Cheema, U., & Moeendarbary, E. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202201749 · Cited by 28 · cited 1× · see citing works
“Although in most cases, clinical trials of these compounds have not shown the expected results [134], current inhibitors targeting MMPs can be divided into two main categories: direct inhibitors and indirect inhibitors.”
Cancer cell migration in collagen-hyaluronan composite extracellular matrices
Veettil, S. R. U., Hwang, D., Correia, J., Bartlett, M. D., & Schneider, I. C. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.06.009 · Cited by 27 · see citing works
Mei, Y., Qin, X., Yang, Z., Song, S., Liu, X., Wu, C., Qian, J., Huang, X., Zhang, Y., & He, W. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.10.003 · Cited by 26 · cited 1× · see citing works
“Treatment of KRAS-TP53 co-mutations in gastrointestinal cancers by inhibition of mutant KRAS and mutant p53 signaling [127].”
Fibroblast-mediated uncaging of cancer cells and dynamic evolution of the physical microenvironment
Liu, C., & Mak, M. (2022) · Scientific Reports · doi:10.1038/s41598-021-03134-w · Cited by 25 · cited 1× · see citing works
“The major group of enzymes responsible for the degradation of collagen and other proteins in the ECM is MMP [132].”
Advances in microfluidic 3D cell culture for preclinical drug development
(2022) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2021.07.022 · Cited by 23 · cited 2× · see citing works
“DDR exists in two isoforms: DDR1 and DDR2 [128, 186–189].”
The Rigidity Connection: Matrix Stiffness and Its Impact on Cancer Progression
Yui, A., & Oudin, M. J. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-0394 · Cited by 22 · cited 3× · see citing works
“It has been shown that D-penicillamine is able to complex-ate Lys-derived aldehydes, making them unable to form cross-links [105].”
InfluentialMechanoimmunology in the solid tumor microenvironment
Golo, M., Newman, P. L. H., Kempe, D., & Biro, M. (2024) · Biochemical Society Transactions · doi:10.1042/bst20231427 · Cited by 22 · cited 1× · see citing works
“Thus, when ECM remodeling and stiffness are targeted using LOX, T-cell migration is enhanced, and the effectiveness of anti-PD-1 blockade is improved [82].”
Mo, C., Zhang, Z., Li, Y., Huang, M., Zou, J., Luo, J., Tu, Z., Xu, Y., Ren, X., Ding, K., et al. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00495 · Cited by 21 · cited 1× · see citing works
“5b) [195].”
Linking Matrix Rigidity with EMT and Cancer Invasion
Ros, M., Sala, M., & Saltel, F. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.032 · Cited by 19 · cited 1× · see citing works
“Meanwhile, high matrix stiffness results in TWIST1 nucleus localization and triggers EMT by weakening TWIST1 binding partner G3BP2 interaction [57] and promoting the activation of the EPHA2/LYN complex [58].”
Enukashvily, N. I., Ponomartsev, N. V., Ketkar, A., Suezov, R. V., Chubar, A. V., Prjibelski, A. D., Shafranskaya, D. D., Elmshäuser, S., Keber, C. U., Stefanova, V. N., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05553-1 · Cited by 18 · see citing works
Rozova, V. S., Anwer, A. G., Guller, A., Es, H. A., Khabir, Z., Sokolova, A. I., Gavrilov, M. U., Goldys, E. M., Warkiani, M. E., Thiery, J. P., et al. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009193 · Cited by 16 · cited 1× · see citing works
“Studies have found that on a high hardness matrix (64 kPa) mimicking bone tissue, cells form multicellular clusters and relocate E-cadherin to the cell surface [63].”
Recent progress on the effect of extracellular matrix on occurrence and progression of breast cancer
Yu, T., Zhang, G., Chai, X., Ren, L., Yin, D., & Zhang, C. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122084 · Cited by 16 · see citing works
Research progress of DDR1 inhibitors in the treatment of multiple human diseases
Liu, M., Zhang, J., Li, X., & Wang, Y. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116291 · Cited by 15 · cited 1× · see citing works
“Discoidin domain receptor (DDR) belongs to the family of receptor tyrosine kinases as a non-integrin collagen receptor [183].”
Fibronectin-targeted FUD and PEGylated FUD peptides for fibrotic diseases
Lee, H. J., Tomasini-Johansson, B. R., Gupta, N., & Kwon, G. S. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.06.008 · Cited by 14 · cited 2× · see citing works
“It can reduce excessive ECM accumulation [121].”
Flagged first, then by citations
Cited by
Sorted by citations
Shah, S., & D’Souza, G. G. M. (2025) · Cells · doi:10.3390/cells14100732 · Cited by 66 · see citing works
“In these settings, increased stiffness not only impedes drug penetration but also fosters an aggressive tumor phenotype and enhances resistance to chemotherapeutic agents [92,98].”
Recent progress in immune evasion mechanisms of triple-negative breast cancer
Yang, Y., & Wang, W. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07370-w · Cited by 50 · see citing works
The extracellular matrix in inflammation and cancer
Zhang, W., Xiang, Y., Lu, C., Wang, F., Ren, H., Wu, H., & Yan, M. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00415-6 · Cited by 32 · see citing works
Tumor microenvironment in breast cancer: cellular crosstalk, pathways, and therapeutic insights
Sharma, M., Kumar, U., & Singh, S. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-11231-6 · Cited by 20 · see citing works
Targeting angiogenesis: Lessons from 25 years of normalizing tumor vasculature
Subudhi, S., Lee, S., & Jain, R. K. (2026) · Cell · doi:10.1016/j.cell.2026.03.016 · Cited by 21 · see citing works
Harnessing Organoid Platforms for Nanoparticle Drug Development
Chen, L., Luo, X., Zhang, J., Zhang, J., Yang, C., & Zhao, Y. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s530999 · Cited by 19 · see citing works
“18 The stiffness is mainly dictated by the quantity and cross-linking extent of stromal components, which are crucial factors influencing tissue stiffness.”
Liu, L., Li, Y., Li, H., Shang, T., & Liu, L. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5824 · Cited by 19 · see citing works
“Moreover, physical barriers within the TME, such as a dense ECM and poor vascularization, can prevent immune cells from infiltrating the tumor (64).”
Targeting tumor microenvironmental barriers to enhance immunogenic cell death in solid tumors
Zhang, J., Han, W., Zhang, M., Yi, Y., & Long, M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1672601 · Cited by 16 · see citing works
Strategies for Pancreatic Cancer-Responsive Nanodrug Platforms Targeting Tumor Hypoxic Environments
Joo, K. S., Sym, S. J., Kim, K., & Khang, D. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s548825 · Cited by 16 · see citing works
“32,34 Essentially, as the ECM stiffens, it not only squeezes vessels shut, but also limits oxygen penetration into tissues by increasing the diffusion distance and creating a gradient where oxygen is rapidly consumed at the periphery of stromal bundles and cannot reach the tumor core.”
Ren, T., Sun, L., Zheng, Y., Jiang, Y., Guo, Y., & Ma, J. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000002636 · Cited by 15 · see citing works
Nanotechnology Meets the Tumor Microenvironment: Unlocking New Horizons in Cancer Therapy
Yadav, P., Yadav, A. K., & Bhatia, D. D. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c01120 · Cited by 16 · see citing works
Kim, D. J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020875 · Cited by 14 · see citing works
“In breast cancer research, hypoxic conditions stimulate LOX , which remodels collagen and creates a pre-metastatic niche in the lung [104].”
He, J., Xue, W., & Li, Y. (2026) · International Journal of Nanomedicine · doi:10.2147/ijn.s560983 · Cited by 16 · see citing works
Zhang, Y., Nie, R., Feng, Z.-Y., Fan, M., Shen, Z., Zhang, X., Zhang, Q., Zou, C., Zhang, J., Huang, K., et al. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.05.026 · Cited by 13 · see citing works
“In addition, analyze the influence of extracellular matrix components (such as fibronectin, laminin, and collagen) on the migration and phagocytosis efficiency of phagocytes in different tissue microenvironments [218].”
Designing immunity with cytokines: A logic-based framework for programmable CAR therapies.
Upadhyay, S., Upmanyu, K., & Gabr, M. (2025) · Cytokine & growth factor reviews · doi:10.1016/j.cytogfr.2025.09.004 · Cited by 14 · see citing works
Yousefi, M., Gharaie, D., Javan, M. R., & Khosrojerdi, A. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115986 · Cited by 15 · see citing works
Chen, P., Chen, J., Zhan, P., Ye, X., Zhao, L., Zhang, Z., Zuo, J., Shi, H., Li, X., Wu, S., et al. (2025) · Cancers · doi:10.3390/cancers18010151 · Cited by 13 · see citing works
“The CAF-dominated dense ECM limits drug penetration, whereas systemic inhibition of the CAF–ECM axis risks disrupting ECM-dependent tissue homeostasis and structural integrity [160].”
The tumor microenvironment: adding pieces to the puzzle
Aguilar‐Cázares, D., Perez-Medina, M., Benito-Lopez, J. J., Galicia-Velasco, M., Meneses-Flores, M., Camarena, Á., & López-González, J. S. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1731338 · Cited by 13 · see citing works
“These changes raise tissue stiffness into the 1 – 10 kPa range, comparable to fi brotic organs, creating physical corridors that redirect or fully prevent lymphocyte in fi ltration (136).”
Host-microbiota interactions in genitourinary cancer immunotherapy
Xu, X., Cui, J., Li, W., Xu, Y., Yuan, S., Zeng, X., & Li, B. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.07.005 · Cited by 10 · see citing works
Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy
Liu, Y., Sun, D., Li, W., Zhang, Z., Li, C., Che, X., & Zhang, S. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114587 · Cited by 10 · see citing works
Fibroblast–immune crosstalk in oral squamous cell carcinoma: from tumor promotion to immune evasion
Liu, X., Wang, D., Cheng, X., Ma, Y., Li, S., Deng, J., & Qiao, C. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1703277 · Cited by 11 · see citing works
Li, H., Zhao, L., Li, J.-W., Zhang, K.-L., Bai, W., & Chen, Y. (2025) · Cell Biology and Toxicology · doi:10.1007/s10565-025-10035-5 · Cited by 7 · see citing works
“Previous studies have demonstrated that the TME is essential for tumor progression, metastasis, and the efficacy of treatment (Xiao and Yu 2021, Zhang and Zhang 2025).”
Translational drugs targeting cancer stem cells in triple-negative breast cancer
de Oliveira, F. P., Nogueira, M. L., Galvão, A. F. C., Dias, R. B., & Bezerra, D. P. (2025) · Molecular Therapy Oncology · doi:10.1016/j.omton.2025.201008 · Cited by 8 · see citing works
ECM Mechanics Control Jamming-to-Unjamming Transition of Cancer Cells
Mierke, C. T. (2025) · Cells · doi:10.3390/cells14130943 · Cited by 8 · see citing works
A biofabricated 3D cancer-stroma tumor microenvironment model
Romanazzo, S., Tian, P., Jalandhra, G. K., Doshi, R. B., Gooding, J. J., & Kilian, K. A. (2025) · Biofabrication · doi:10.1088/1758-5090/ae0a82 · Cited by 8 · see citing works
“CAFs have also been shown to induce local matrix stiffening [45, 46], which may further influence cancer cell invasion; however, investigating matrix stiffening within embedded microgels presents technical challenges and remains an avenue for future study.”
The tumor ecosystem: Rewiring an open, systemically integrated network for therapeutic gain
Chiodelli, P., Papait, A., Agoni, L., Quaglia, F., Silini, A. R., & Parolini, O. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119047 · Cited by 10 · see citing works
Exploring the Tumor Microenvironment in Osteosarcoma: Driver of Resistance and Progression
Schmidt, A. A., Prasad, A., Huisman, A. R., Wakefield, M. R., & Fang, Y. (2025) · Cancers · doi:10.3390/cancers17193106 · Cited by 9 · see citing works
“As has been previously discussed, ECM in OS is stiffer than baseline forms [172], allowing for MRTF-A upregulation and a higher metastatic potential [20,175].”
Mechano-regulation of cancer cell memory in tumor progression and therapy
Qu, Y., Cui, J., Wu, Z., He, P., Wei, F., Guo, T., Huang, Y., Yu, X., Tsoy, M., Liu, K., et al. (2025) · Mechanobiology in Medicine · doi:10.1016/j.mbm.2025.100165 · Cited by 7 · see citing works
“13,57,58 Notably, such stiffness-induced check-point upregulation can persist even when ECM stiffness is partially normalized, 59 indicating a hysteretic form of mechanomemory that locks tumors into an immune-evasive state.”
The importance of mechanical forces in chronic respiratory diseases
Burgess, J. K., Nawroth, J. C., Ibáñez‐Fonseca, A., & Gavara, N. (2026) · European Respiratory Review · doi:10.1183/16000617.0155-2025 · Cited by 9 · see citing works
“Alveolar epithelial cells may also become affected by the increased rigidity, undergoing epithelial – mesenchymal transition (EMT), a phenomenon also observed in cancer that contributes to tissue fibrosis [90, 91].”
Stem Cell-Derived Organoids for Cancer Therapy: Precision Medicine and Drug Selection
Azim, M. M. N., Bhajan, S. K., Park, J. H., Abass, K. S., Rahman, A., Choi, M., Choi, J., Park, S., Kim, H. J., Akter, S., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27072954 · Cited by 7 · see citing works
Park, Y., Kang, D. H., & Chung, C. (2025) · Lung Cancer · doi:10.1016/j.lungcan.2025.108726 · Cited by 6 · see citing works
Targeting cytokines: Reshaping the pancreatic tumor microenvironment
Bandi, D. S. R., Chabattula, S. C., Pynam, H., Joseph, J. T., Sarvesh, S., Nagaraju, G. P., & El‐Rayes, B. F. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.11.003 · Cited by 6 · see citing works
Molecular Mechanisms Driving Metastatic Progression Within the Aged Tumor Microenvironment
Kumar, S., Chand, J., Sharma, P., Singh, S., Khanal, P., Chellammal, H. S. J., Suhail, A., & Mittal, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311508 · Cited by 6 · see citing works
“In the aged TME, metastatic progression is driven by a complex interplay of molecular pathways stemming from age-related cellular and tissue dysfunction [32–34].”
Cicero, A. L., Monica, F. L., Buglio, G. L., Campora, S., Gangemi, F., Paolo, C., Salamone, M., Pinto, M. L., Scilabra, S. D., & Ghersi, G. (2026) · Cancer Cell International · doi:10.1186/s12935-025-04154-6 · Cited by 6 · see citing works
“This molecular profile mirrors the dynamic nature of in vivo tumor progression, where ECM degradation facilitates angiogenesis, tumor invasion, and metastasis [46].”
The Heterogeneity and Function of Stromal Cells in the Tumor Microenvironment
Wang, X., Li, S., Xue, Y., Liang, X., Ma, X., Zhang, K., & Wang, Y. (2026) · Research · doi:10.34133/research.1183 · Cited by 7 · see citing works
“These matrix changes increase stiffness and IFP, further hindering convection and diffusion of therapeutics into tumor parenchyma [ 141 ].”
Heydari, F., Zendehdel, H., Varkiani, M. M., Fahmi, S., Derakhshani, M., Anvari, S., Farhid, F., Hamblin, M. R., & Naghinezhad, J. (2026) · Biomarker Research · doi:10.1186/s40364-026-00957-5 · Cited by 7 · see citing works
Xie, S.-A., Li, X., Yin, M., Du, F., Zhang, S., & Zhu, S. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00704-w · Cited by 5 · see citing works
“Mechanical signals stemming from matrix stiffness can be translated into biological signals via mechanical sensors or transducers to regulate tumor-associated gene expression [7–10].”
Multilayered microfluidic platform for three-dimensional vascularized organ-on-a-chip applications
Zhou, C., Li, Z., Xu, J., Yu, D., Xuan, L., & Wang, X. (2025) · Bio-Design and Manufacturing · doi:10.1631/bdm.2500091 · Cited by 6 · see citing works
“The biomechanical properties of the ECM, particularly stiffness, serve as critical regulators of tumor progression and angiogenic dynamics [49].”
Leonteva, A. A., Kazakova, A., Berezutskaya, E., Ilyina, A., Sergeevichev, D., Vladimirov, S., Bogachek, M. V., Vakhrushev, I. V., Макаревич, П. И., Richter, V. A., et al. (2026) · Cells · doi:10.3390/cells15020145 · Cited by 5 · see citing works
“Fibroblast activation and increased https://doi.org/10.3390/cells15020145 ECM stiffness create a feedback loop within the tumor microenvironment that promotes cancer cell invasion and migration [73].”
InfluentialBhalotia, A., Hutchinson, D. W., Kosmides, T., Nittayacharn, P., Mehta, M., Iyer, A., Cheplyansky, A., Takizawa, K., Nidhiry, A., Dever, A. M., et al. (2026) · ACS Nano · doi:10.1021/acsnano.5c21787 · Cited by 5 · see citing works
Impact of mechanical property alterations on cancer cell motility and metastasis
Belousova, P., Kwon, S., Jung, M., & Kim, K. S. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105165 · Cited by 6 · see citing works
Basem, Y., Ata, A., Sherif, A., Abdel-Ghany, S. E., Arneth, B. M., & Sabit, H. (2026) · Pharmaceuticals · doi:10.3390/ph19040541 · Cited by 5 · see citing works
“LOX cross-linking increases ECM stiffness, activates integrin–FAK–SRC and PI3K–AKT signaling, and reduces T-cell motility, establishing a biophysical mechanism for immune exclusion and pharmacokinetic resistance [85].”
Rizkallah, J., Wehbeh, B. E. D., Wassouf, W., Salameh, E., Joumaa, A., Haddad, F. J., Hamade, L., Charbel, N., Bakri, G. M., Awada, A., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1800292 · Cited by 6 · see citing works
“Furthermore, collagen rearrangement promotes ECM protein accumulation, increasing matrix density and organization (84).”
Wu, Z., Zeng, B., Seah, D. H., Ng, I. Z. R., Ding, R. H., Zhang, T., Kalaichelvan, M., You, R., & Fong, E. L. S. (2025) · Advanced Materials · doi:10.1002/adma.202512252 · Cited by 4 · see citing works
Crintea, A., Constantin, A.-M., Jianu, M. E., Orlea, I. M., Manea, M. M., Cojocariu, R. O., Carpa, R., Borlea, B., Boznea, C.-M., Coșeriu, R. L., et al. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17121579 · Cited by 4 · see citing works
“The TME also contains many immunosuppressive cells, which makes the effect of immunotherapy more difficult [163,164].”
Sabu, A., Yang, Y., Sarma, R. R., Ramesan, L., Lin, Y.-H., & Chiu, H. (2025) · Biomaterials Advances · doi:10.1016/j.bioadv.2025.214677 · Cited by 4 · see citing works
Mechano-Organ-on-Chip for Cancer Research
Wang, L., Cheung, J. C., Zhao, X., Khoo, B. L., & Wong, S. H. D. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031330 · Cited by 7 · see citing works
“Changes in matrix viscoelasticity also modulate cell mechanosensing and behavior [29,30].”
Muñoz-Villaescusa, C., van der Ven, D. L., Quetzeri-Santiago, M. A., & Rivas, D. F. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115792 · Cited by 4 · see citing works
Hall, M. H., Amobi, O., Khalaf, J., Afees, O. J., & Brantley, E. J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031510 · Cited by 4 · see citing works
“In general, ECM stiffness is higher in breast cancer tissue than in normal tissue and acts as a barrier to drug delivery [62].”
Hao, J., Zakershahrak, M., Ly, P., Le, A. D., Yu, W., Gates, J. C., & Chen, C. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07786-y · Cited by 5 · see citing works
“However, with FAP degrading collagen and increasing stiffness, FAP serves as a biomarker for a TME and for therapeutic resistance [85].”
Shabib, M., Kumari, M., Gupta, U., Dan, S., Mandal, C., Kaity, S., & Roy, S. (2026) · ACS Applied Bio Materials · doi:10.1021/acsabm.5c02380 · Cited by 4 · see citing works
Tinhofer, I., & Fisch, A.-S. (2026) · Current Opinion in Oncology · doi:10.1097/cco.0000000000001212 · Cited by 4 · see citing works
Choi, S. R., Mellican, S., Roberts, T. J., Kang, S., Elzey, B. D., Kong, H., Davis, C. S., Fishel, M. L., Flick, M. J., Wolberg, A. S., et al. (2026) · Acta Biomaterialia · doi:10.1016/j.actbio.2026.03.023 · Cited by 4 · see citing works
“Moreover, both cancer cells and activated CAFs can further reorganize the stroma by secreting matrix-degrading enzymes like matrix metalloproteinase and upregulating tissue inhibitor of metalloproteinases, driving fibro-genesis and tumor progression [62,65].”
Pigoń-Zając, D., Bryczek, M., Leszczuk, A., & Zając, A. (2026) · Cells · doi:10.3390/cells15110997 · Cited by 4 · see citing works
Cai, H., Shen, D., Hu, X., Yin, H., & Yan, Z. (2025) · Toxins · doi:10.3390/toxins17080388 · Cited by 4 · see citing works
Telomere maintenance meets cancer metabolism: Mechanistic insights and clinical opportunities
Sung, J., & Hwang, K. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.105017 · Cited by 4 · see citing works
The Significance of the Microenvironment in T/Nk-Cell Neoplasms
Petković, I., Ritucci, M., Stojković, A., Stojnev, S., Popović, A., Conić, I., Radić, M., Džunić, M., & Krstić, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211225 · Cited by 3 · see citing works
“…associated with the vasculature, together with acellular matrix compounds and the cytokine milieu, establish a complex, dynamic network that modulates signaling pathways, local metabolism, mechanical support, and immune responses, thereby exerting profound influence on lymphoma cell behavior [17].”
Yin, M., Li, X., Zhang, S., & Xie, S.-A. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-11283-8 · Cited by 3 · see citing works
Cui, S., Chen, X., Qian, C., Wu, C., Wang, J., Zhang, Y., & Xiang, D. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.172183 · Cited by 3 · see citing works
Cai, H., Hu, G., Chen, J., Feng, H., & Bi, Y.-H. (2026) · BMC Cancer · doi:10.1186/s12885-025-15472-3 · Cited by 3 · see citing works
“Recent studies have revealed that PLOD enzymes not only contribute to ECM remodeling but also influence cancer progression through mechanisms such as tumor cell migration, invasion, angiogenesis, and regulation of the hypoxic response [15, 16].”
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“The ToC platform was first optimized using the HBCx-14 model by testing a range of collagen properties, including ECM stiffness and cell crowding, given that the TME is typically stiffer 45 and denser in cells than healthy tissues.”
- Authors
- Zhang, M., & Zhang, B.
- Affiliations
- China Three Gorges University (CN)
- Corresponding author
- Zhang, Bin
- Venue
- Experimental Hematology & Oncology
- Published
- 2025-04-10
- Volume
- 14
- Issue
- 1
- Pages
- 54-54
- ISSN
- 2162-3619 (ISSN-L)
- PMC
- PMC11984264
- OpenAlex
- W4409339209
- Cited by
- 269
- References
- 205
- Citations by year
- 2026: 199 · 2025: 70
- FWCI
- 32.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Experimental Hematology and Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- extracellular matrix stiffness, tumor microenvironment, tumor progression, mechanotransduction, metastasis, drug resistance, angiogenesis, epithelial-mesenchymal transition, immune evasion, cancer stemness, metabolic reprogramming, genome stability
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