Extracellular matrix stiffness: mechanisms in tumor progression and therapeutic potential in cancer

“Indirect MMP inhibitors include blockade of signal transduction pathways (such as MAPK or ERK pathways [141]), and gene therapy (such as inhibition of miRNA expression [51]) to achieve the inhibition of MMP [142].”

“For example, breast cancer cells under high tension can enhance integrin-dependent mechanical signaling through the expression of FAK or p130cas, which are two integrin-adhesion focal proteins, and promote the progression of breast tumors [39].”

“For example, breast cancer tissue (5–10 kPa) is stiffer than normal breast tissue (800 Pa) [9].”

“CAFs are key components of the TME [128], which can enhance the ECM stiffness by the secretion of collagen and other fibrous macromolecules, as well as the degradation of this network through the release of proteolytic enzymes like MMPs, thereby improving the cellular mobility of the entire ECM…”

“In certain scenarios, altered metabolic activity resulting from reprogramming can be utilized for diagnosing, monitoring, and treating cancer [101].”

“A low number of myofibroblasts in the tumor is also associated with reduced survival in PDAC patients [130].”

“The oncogene Ras promotes the ameboid migratory phenotype by stimulating Rho activity, whereas the tumor suppressor p53 reduces tumor cell migration by decreasing RhoA activity [41].”

“YAP is required for CAFs to promote matrix sclerosis, acting as a marker of CAFs at early tumor stages and as an inducer of mechanical activation of CAF function [5].”

“…human HYAL, which can break down HA and be used to enhance drug delivery, has recently entered clinical trials; for example, enzymatic HA partially restores impaired perfusion of hepatic MCCs after anti-VEGF therapy and prolongs survival when combined with anti-VEGF therapy and chemotherapy [45].”

“To overcome the solubility factor, another hydroxylate-based inhibitor, marimastat, was introduced for oral administration; however, marimastat showed musculoskeletal pain, possibly due to a wide range of inhibition [136].”

“…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].”

“Elevated ECM stiffness activates cellular responses through mechanical signal transduction pathways, such as Integrin/FAK and YAP/ TAZ signaling pathways [6], driving tumor evolution to a malignant phenotype [7, 8].”

“Indirect MMP inhibitors include blockade of signal transduction pathways (such as MAPK or ERK pathways [141]), and gene therapy (such as inhibition of miRNA expression [51]) to achieve the inhibition of MMP [142].”

“Changes in matrix composition or stiffness, cytokines, growth factors, integrins, and pH trigger FAK activity through the αvβ5/FAK/PI3K/Akt signaling pathway [146] to prevent anoikis and other types of cell death.”

“In addition, specific proteins such as OPN play a key role in EGFR-TKI resistance by activating the integrin αVβ3/ FAK pathway in non-small cell lung cancer [75].”

“Instead, studies have found that blocking the interaction between integrins, particularly those rich in αv subunits, maybe a more effective approach [143].”

“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].”

“…carcinoma TAS-001 An antisense oligonucleotide specifically targeting TGF-β2 is employed in the treatment of advanced or metastatic solid tumors [181] Small-molecule receptor kinase inhibitors Galunisertib An oral small-molecule TGF-βRI tyrosine kinase inhibitor that down-regulates SMAD2…”

“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].”

“…are key components of the TME [128], which can enhance the ECM stiffness by the secretion of collagen and other fibrous macromolecules, as well as the degradation of this network through the release of proteolytic enzymes like MMPs, thereby improving the cellular mobility of the entire ECM [129].”

“Consider neovastat compound extracted from shark cartilage, which inhibits not only MMP enzyme activity but also VEGF [140].”

“The reason is that tumor tissues with higher stiffness not only highly express key molecules essential to EMT induced by stiffness [55] but also induce EMT by activating the FAK/Src signaling pathway and stimulating the expression of receptor tyros-ine-protein phosphatase kappa [56].”

“Meanwhile, high matrix stiffness enhances the nuclear localization of TWIST1 by freeing it from its cytoplasmic binding partner G3BP2 [48], and induces EMT to promote tumor invasion and metastasis [49].”

“Similarly, EDB can also be used as a target for antibody-mediated radioisotope delivery, and fusion protein I labeling of L19 and small immune protein can not only slow tumor growth but also prolong the survival of F9 teratoma and head and neck cancer xenograft mice [8].”

“…conditions, MSCs can be induced to an osteogenic phenotype and produce significantly high levels of RUNX2, alkaline phosphatase (ALP), and OPN, and the cell morphology is polygonal and spreads over a larger area [92], while the lower stiffness matrix promotes adipocyte differentiation [93].”

“The first MMP inhibitor to enter clinical trials was batimastat, a low molecular weight hydroxamic acid derivative with low water solubility that inhibits a variety of MMPs [135].”

“In addition, different types of collagen exhibit different resistance mechanisms, such as COLI through activation of β1 integrin and multiple signaling pathways, and COLI and ColVI-induced tau upregulation leading to resistance to multiple drugs [40].”

“Notably, it has been shown that reducing ECM stiffness not only induces tumor cells to enter a resting state, but also reduces tumor cell spreading area, stress fibers, and focal adhesion, inhibits cell proliferation without inducing apoptosis, and exhibits stronger stem cell properties [29].”

“…b l e A n t i fi b r o t i c a g e n t a d m i n i s t e r e d fi r s t t o d o w n - r e g u l a t e C A F a c t i v i t y f o ll o w e d b y a d m i n i s t r a t i o n o f d o c e t a x e l m i c e ll e s t o p r o d u c e a s y n - e r g i s t i c a n t i t u m o r e ff e c t [ 172 ] F r a x -”

“This signaling network leads to overactivation of the Ras-MAPK pathway, which supports the growth and maintenance of an invasive phenotype of mammary epithelial cells in vitro and in vivo [36].”

“MMPs are involved in tumor invasion, angiogenesis, and metastasis, thus rendering them ideal pharmacological targets for cancer therapy [133].”

“3a) [100].”

“Experimental models have shown that conditionally activated ROCK2 can increase tissue stiffness by increasing collagen, which further activates nuclear transcriptional activity by stabilizing β-catenin [28], leading to excessive cell proliferation and tissue thickening [28].”

“They further organize the FN matrix by augmenting nonmuscle myosin II and PDGFRα-mediated contractile and traction forces that are transmitted to FN through α5β1 integrin [44].”

“The opposite process, termed mesenchymal-epithelial transition (MET), is commonly seen in developmental stages such as the development of the heart, renal morphogenesis, somatization, and cancer [53].”

“Inhibition of LOX can weaken the fibrillar collagen network and improve the pathway of T cells into the tumor [79].”

“Rho-associated protein kinase (ROCK) is an important mechanosensor between matrix stiffness and tumor cells [18].”

“…e n ) , a n t i h y p e r t e n s i v e s ( l o s a r t a n , b o s e n t a n ) , a n d c o r t i c o s t e r o i d s ( d e x a m e t h a s o n e )[ 162 ] M o n o c l o n a l A n t i b o d i e s M a b F 19 ( S i b r o t u z u m a b ) T h e s e b i n d w i t h h i g h a ffi n i t y t o s u r f a c…”

“In line with this, the mechanical therapy tranilast, combined with immune checkpoint inhibition, helps restore TME abnormalities, in combination with inhibition of the immune checkpoint, increased T-cell infiltration in the TME and immune memory in breast cancer mice resistant to immunotherapy [83].”

“Compounds that target FAK can be divided into ATP-competitive kinase inhibitors (KI), molecules that block FAK catalytic activity by alternative means (aKI), and compounds that target FAK scaffolds (scaffold inhibitors, SI) [147].”

“Normal hepatic tissue has a stiffness of less than 6 kPa, while values higher than 8–12 kPa are indicative of conditions such as fibrosis or cirrhosis that may result in the development of liver cancer (HCC) [10].”

“In addition, LMW HA stimulates the expression of MMPs, thereby favoring tumor cell invasion and angiogenesis [69].”

“…to LOX-catalyzed generation, collagen cross-linking can also occur through non-enzymatic pathways, such as the formation and accumulation of AGEs [117], which are formed by the reaction between the reducing carbonyl groups of sugars and the free ε-amino groups of proteins (such as the ε-amino…”

“In addition, TAGLN was identified as a potent mechanosensitive gene that mediates ovarian cancer cell migration and invasion in response to stiffness by regulating the RhoA/ROCK pathway in a feedback loop through binding to Src activation [42].”

“…e l - l e n t t h e r a p e u t i c e ffi c a c y a n d d u r a b l e t u m o r s u pp r e ss i o n i n x e n o - g r a f t m o u s e m o d e l s [ 164 ] R O 6874281 F A P - t a r g e t i n g a n t i b o d y , w h i c h b i n d s t o F A P w i t h h i g h a ffi n i t y , i s c u rr e n t l y u n…”

“Important metabolic pathways, such as aerobic glycolysis, glutaminolysis, macromolecular synthesis, and redox homeostasis, are crucial for cancer cell progression [7].”

“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].”

“…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] Monoclonal Antibodies 1D11 A pan-neutralizing antibody against mouse TGF-β binding to three TGF-β isoforms, reducing their biological activity…”

“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].”

“…l o a d e d w i t h s i R N A t o s i l e n c e o n c o g e n i c K R A S m u t a t i o n s a n d e ff e c t i v e l y k i ll c a n c e r c e ll s [ 173 ] L o s a r t a n A n g i o t e n s i n II a n t a g o n i s t , w h i c h i m p r o v e s t h e T M E b y p r e - i n j e c - t i o n o f l o s…”

“ECM stiffness and composition act as a physical barrier [78] to hinder the infiltration of immune cells into the TME through a variety of physical and chemical mechanisms, and fine-regulate the migration and localization of immune cells.”

“TGF-β inhibitors not only normalize tumor stroma by reducing collagen I content but also improve the ability of other anticancer drugs to penetrate tumors more effectively [131], resulting in a significant reduction in tumor growth and metastasis.”

“For example, matrix stiffness can not only regulate macrophage polarization by regulating YAP expression and nuclear localization [86] but also regulate mitochondrial ROS production through the Rho pathway, which in turn triggers the NF-κB pathway to regulate macrophage polarization.”

“TIMP is a natural inhibitor of MMPs [137], but due to its low bioavailability, potential side effects, and toxicity, its clinical application is limited and it has not been widely used to inhibit MMPs in clinical practice [139].”

“AGEs indirectly influence collagen formation and diminish NO bioavailability, thereby promoting collagen cross-linking [118].”

“Another drug targeting the hydrophobic pocket of TEAD is VT3989 developed by Vivace Therapeutics, which has entered Phase I clinical trials (NCT04665206) for the treatment of NF2 mutated solid tumors and mesothelioma [153].”

“FN, a glycoprotein present in blood and tissues, plays a key role in matrix deposition by interacting with cellular and extracellular components [120].”

“Similarly, some natural ECM-derived hydrogels (such as collagen hydrogels) are expensive, lack reproducibility, and require extensive handling and specific equipment [198].”

“Several preliminary reports have suggested that the addition of HYAL to chemotherapy regimens can significantly improve efficacy; for example, expression of the wild-type HYAL-1 variant triggers apoptosis in bladder cancer cells by inducing a G2-M phase arrest [124].”

“Mechanistic studies confirmed that ECM stiffness enhances the activity of DCs by activating TAZ and calcium channels (such as PIEZO1) in the Hippo signaling pathway, thereby triggering an adaptive immune response [89].”

“…conditions, MSCs can be induced to an osteogenic phenotype and produce significantly high levels of RUNX2, alkaline phosphatase (ALP), and OPN, and the cell morphology is polygonal and spreads over a larger area [92], while the lower stiffness matrix promotes adipocyte differentiation [93].”

“At present, it has been shown that the effect of ECM stiffness on tumor progression is not only related to intracellular signaling but also involves extracellular vesicles such as exosomes [206].”

“DDR exists in two isoforms: DDR1 and DDR2 [128, 186–189].”

“On the contrary, at moderate matrix stiffness, macrophages express more CD206, produce less ROS, secrete more anti-inflammatory factors, and promote the polarization of alternative activated M2 macrophages, thereby inhibiting the inflammatory response [88].”

“For example, the drug named HYTAD1-p20 conjugated with HA-PTX can effectively inhibit cell mitosis [126].”

“Specifically, high matrix stiffness can activate fibroblasts, leading to the secretion of collagen, FN, GAGs, and other components, thus forming a positive cycle [16].”

“Abnormal genomic stability can lead to the accumulation of mutations and chromosomal aberrations, which are closely related to cancer, aging and genetic diseases [104].”

“The reason is that tumor tissues with higher stiffness not only highly express key molecules essential to EMT induced by stiffness [55] but also induce EMT by activating the FAK/Src signaling pathway and stimulating the expression of receptor tyros-ine-protein phosphatase kappa [56].”

“F A P a n t i b o d y ,, w a s u s e d i n a P h a s e I c l i n i c a l t r i a l a n d s h o w e d s a f e t y a n d m o d e s t e ffi c a c y , b u t d i d n o t m ee t t h e r e q u i r e m e n t s f o r a p a r t i a l o r c o m p l e t e r e s p o n s e [ 163 ] M A b F A P 5 -”

“In addition, collagen itself also trans-mits signals to cells through receptors such as DDR1 and DDR2, and the activation of DDR2 stabilizes SNAIL1 and promotes the EMT process [48].”

“Increasing works have focused on the role of ECM stiffness in the EMT of cancer cells [54].”

“2) [25].”

“This double inhibition is effective in preventing pathologic collagen-related accumulation but does not have the toxic effect of global inhibitors [115].”

“Quantitatively, this property is assessed using the elastic modulus [4].”

“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.”

“Notably, YAP and TAZ are transcriptional coactivators not only of TEAD but also of AP-1, CKB [154] and STAT3 [18].”

“…[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 Fc fusion protein incorporating the soluble ectodomain of TβRII has been shown to reduce the incidence of mammary tumor…”

“Under normal conditions, angiogenesis is tightly regulated, but in the TME, the formed tumor blood vessels are usually disorganized, leaky, and inefficient, leading to inefficient drug delivery and loss of therapeutic effect [64].”

“…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].”

“…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 a d v a n c e d T N B C , h a s s h o w n s o m e a n t i t u m o r a c t i v - i t y [ 161 ] P i r f e n i d o n e T a r g e t i n g T G F - β p a t h w a y a c t i v a t i o n i n C A F s h a s b ee n d e m o n - s t r a t e d t o e nh…”

“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 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].”

“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].”

“It has been reported to inhibit liver metastasis and improve survival in mouse models [138].”

“Inhibiting FAK signaling may increase the susceptibility of PC9 gene resistance to EGFR-TKI in vitro and in vivo experiments [34].”

“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].”

“In HCC cells, higher matrix stiffness significantly upregulates the expression of LOXL2 by activating the integrin β1/α5/JNK/c-JUN signaling pathway [27].”

“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].”

“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].”

“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].”

“Among them, synthetic hydrogels can simulate the ECM of the human body, while avoiding the problems of heterogenicity and batch differences of natural materials [201].”

“When cancer cells invade, they must be squeezed through narrower pores and undergo more physical damage [97].”

“Normal healthy pancreas tissue has a stiffness of 1–3 kPa, whereas pancreatic carcinoma tissue has a stiffness of over 4 kPa [11, 12].”

“This extrusion motion would allow some mobile proteins to be separated from DNA205 [106].”

“MMPs can degrade the matrix components, promote EC migration, and provide space for creating a new vascular sys-tem [68].”

“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.”

“…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 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].”

“Collagen cross-linking is almost exclusively mediated by LOX [24], a copper-dependent, secreted amino oxidase encoded by the PLOD family.”

“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.”

“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].”

“Increased matrix stiffness enhances PD-L1 expression in cancer cells [81], which was associated with nuclear translocation of YAP/TAZ.”

“3) [35].”

“These enzymes are found in a wide range of tissues and organs, such as aorta, heart, lung, and brain [26].”

“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].”

“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).”

“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].”

“Integrins process biochemical and mechanical signals between cells and their environment in a variety of health and disease states [90].”

“Its mechanism of action is to activate cannabinoid receptor 2, leading to the production of prostaglandins, which reduce inflammatory cytokines and fibrosis [109].”

“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].”

“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].”

“…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]…”

“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].”

“…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].”

“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].”

“Chloropyramine hydrochloride inhibits the proliferation and growth of cancer cells by inhibiting VEGFR-3 and FAK signaling [149].”

“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].”

“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].”

“…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.”

“Unfortunately, prinomastat failed in Phase III trials owing to its ineffectiveness in patients with advanced disease [21].”

“DDR1 is broadly expressed in epithelial cells, whereas DDR2 is predominantly found in mesenchymal cells [185].”

“In addition, β1-integrin and FAK are also involved in the stiffness-dependent regulation of HCC cell proliferation [30].”

“Thus, angiogenesis is promoted [66].”

“…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].”

“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].”

“…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].”

“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.”

“Normal healthy pancreas tissue has a stiffness of 1–3 kPa, whereas pancreatic carcinoma tissue has a stiffness of over 4 kPa [11, 12].”

“The soft matrix induces early G1 phase arrest of the cell cycle and enhances the ability of spheroid formation [33].”

“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].”

“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].”

“Emerging studies have demonstrated that DDR1 is a key regulator of cancer genesis, differentiation, migration, and invasion [191].”

“4b) [76].”

“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.”

“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…”

“Their activation positively correlates with malignancy, recurrence, metastasis, reduced overall survival, and drug resistance [150].”

“D-penicillamine has been used to treat diseases with collagen accumulation, such as liver fibrosis and progressive systemic sclerosis [116].”

“…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.”

“…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…”

“…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].”

“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].”

“One of the most fundamental biological processes in tumor metastasis is the EMT process [52].”

“…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…”

“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].”

“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].”

“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].”

“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].”

“…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.”

“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].”

“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.”

“Treatment of KRAS-TP53 co-mutations in gastrointestinal cancers by inhibition of mutant KRAS and mutant p53 signaling [127].”

“The major group of enzymes responsible for the degradation of collagen and other proteins in the ECM is MMP [132].”

“DDR exists in two isoforms: DDR1 and DDR2 [128, 186–189].”

“It has been shown that D-penicillamine is able to complex-ate Lys-derived aldehydes, making them unable to form cross-links [105].”

“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].”

“5b) [195].”

“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].”

“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].”

“Discoidin domain receptor (DDR) belongs to the family of receptor tyrosine kinases as a non-integrin collagen receptor [183].”

“It can reduce excessive ECM accumulation [121].”

“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].”