The story begins with the pulp–dentin complex itself, the integrated functional unit that keeps a living tooth alive. Odontoblasts line the periphery of the pulp space and extend processes into the dentinal tubules, serving as sentinels that detect external threats and deposit tertiary dentin as a defensive barrier. Fibroblasts, the most abundant stromal cells in the pulp, produce and maintain the extracellular matrix, while dental pulp stromal cells, or DPSCs, carry remarkable regenerative and immunomodulatory properties, including the ability to differentiate into odontoblast-like cells and contribute to reparative dentin formation. When caries breaches the enamel and advances through dentin, a dynamic network of interdependent relationships emerges among odontoblasts, stromal cells and immune cells, and it is within this network that the Korean team went hunting for the rules of communication.

Macrophages were the obvious suspects. These innate immune cells are the pulp’s frontline defenders, recognizing pathogen-associated molecular patterns through Toll-like receptors and mounting inflammatory responses against bacterial invasion. But macrophages are also indispensable mediators of tissue remodeling, secreting trophic factors such as TGF-beta, VEGF and IGF-1 that regulate the proliferation, migration and differentiation of resident progenitor cells. To see how macrophages behave during actual disease, the researchers examined human dental pulp tissue from healthy teeth and teeth with moderate or severe caries, using immunofluorescence to track CD68-positive macrophages. In healthy pulp, macrophages were sparsely distributed throughout the tissue. As caries progressed, their numbers surged, and they clustered beneath regions of advanced decay near the odontoblast layer.

The most striking observation was physical contact. The proportion of macrophages in intimate contact with Thy-1-positive DPSCs rose from 11.2 percent in healthy teeth to 23.7 percent in moderate caries and 48.7 percent in severe caries, suggesting that these immune–stromal encounters are not incidental but part of an organized defensive response. In vitro, the team co-cultured differentiated human macrophages with primary DPSCs and watched the two cell types lock together, extending lamellipodia and filopodia-like protrusions visible under scanning electron microscopy. Macrophages in direct contact with DPSCs showed markedly increased filamentous actin intensity, particularly at the cell–cell interface, a hallmark of intercellular adhesion mechanisms at work.

What molecule was doing the gluing? The researchers profiled adhesion components by RNA sequencing and tested two hypotheses: direct homophilic binding between matching cell-adhesion molecules, or indirect communication through an extracellular matrix intermediary. The homophilic route failed, as macrophages and DPSCs showed no matching cadherin or ICAM-family expression patterns. The matrix route, however, lit up. DPSCs predominantly expressed fibronectin and type I collagen, while macrophages abundantly expressed the integrin subunits ITGA5 and ITGB1, the canonical receptors for fibronectin. Computational ligand–receptor prediction with CellPhoneDB confirmed statistically significant interactions between fibronectin on DPSCs and multiple integrin receptors on macrophages. Structured illumination microscopy then revealed that integrin alpha-5 clusters on macrophages aligned precisely with fibronectin deposited on the DPSC surface, forming the activated, clustered configuration characteristic of functional adhesion.

The functional proof was decisive. A synthetic RGD peptide that blocks integrin–ligand binding reduced macrophage–DPSC contact in a concentration-dependent manner, while collagenase treatment had no effect. CRISPR-Cas9 knockout of ITGA5 in macrophages slashed both the proportion and the duration of contacts with DPSCs, as live imaging over 48 hours demonstrated. Downstream, phosphorylated focal adhesion kinase rose in macrophages cultured on fibronectin-coated surfaces and climbed even higher in co-culture, implicating the fibronectin–integrin–FAK axis as the signaling conduit between the two cell types.

Then came the transformation. Bulk RNA sequencing of sorted macrophages revealed that co-culture with DPSCs shifted their chemokine repertoire dramatically: pro-inflammatory CCL2 and CCL3 were downregulated, while a suite of ELR-positive CXC chemokines—CXCL2, CXCL3, CXCL5, CXCL6 and CXCL8—known for their angiogenic activity were upregulated, alongside VEGFA. Macrophages seeded on fibronectin-coated plates upregulated these pro-angiogenic factors in a dose-dependent fashion, and silencing FN1 in DPSCs suppressed the effect, confirming fibronectin as the trigger. Flow cytometry showed the macrophages shifting toward an M2-like phenotype, with CD206 rising while CD86 stayed flat. The mechanism ran through NF-kappa-B: p65 accumulated in both cytoplasm and nucleus of co-cultured macrophages, and a live-cell GFP reporter showed that fibronectin-coated surfaces drove NF-kappa-B activity roughly 90 percent higher than LPS treatment, while collagen 1 surfaces did nothing.

The consequences for blood vessels were immediate. Conditioned medium from macrophage–DPSC co-cultures dramatically enhanced tube formation by human umbilical vein endothelial cells, increasing the number of junctions, segments and meshes compared with medium from either cell type alone. Endothelial cells exposed to co-culture medium also showed fewer apoptotic membrane blebs and reduced cleaved caspase-3, indicating improved survival. Blocking CXCR2 or VEGFR signaling with specific inhibitors attenuated both angiogenesis and endothelial survival, pinning the effect on the newly identified chemokine and VEGF pathways. An integrated single-cell RNA sequencing atlas of nearly 20,000 human pulp cells, analyzed with the CellChat framework, independently confirmed the story in real tissue: as caries progressed from healthy to severe, total cell–cell interactions exploded from 278 to 2,470, macrophage–endothelial CXCL signaling strengthened markedly, and macrophages emerged as central hubs of the angiogenic communication network.

The final test was translational. In a canine model of pulp revascularization using immature premolar teeth, the researchers applied fibronectin as a final canal irrigation and on a collagen sponge scaffold, following American Association of Endodontists guidelines in a split-mouth design with 22 roots per group. Eight weeks later, micro-computed tomography showed that fibronectin-treated roots had significantly greater cross-sectional dentin area (3.40 versus 2.39 square millimeters) and far more frequent apical closure (59.1 percent versus 22.7 percent). Histology revealed organized layers of polarized odontoblast-like cells, dentinal tubule-like structures and dentin sialoprotein-positive staining in the treated roots, along with abundant new blood vessels and CD14-positive, CD163-positive M2 macrophages in the stromal region—precisely the cellular signature the in vitro work had predicted. Fibronectin itself was localized along the regenerated odontoblast layer, mirroring its arrangement in healthy human pulp.

The implications reach well beyond the dental chair. Because fibronectin is an endogenous protein with established biocompatibility, it carries minimal risk of adverse reactions compared with exogenous growth factors or synthetic biomaterials, and its angiogenic capabilities suggest potential applications in soft-tissue regeneration, bone-tissue engineering and scaffold-based therapies across regenerative medicine. For the millions of children and adults with immature necrotic teeth—a population for whom conventional root canals arrest root development and increase fracture risk—the prospect of a simple, biologically grounded irrigation solution that coaxes the body’s own immune and stromal cells into rebuilding a living pulp is genuinely tantalizing. The authors caution that species differences in pulp biology, optimization of delivery parameters and long-term follow-up studies all stand between this canine model and human clinical practice. But the core discovery stands: a humble matrix protein, long viewed as passive scaffolding, is in fact an active conductor of the immune–stromal orchestra that turns a damaged, infected pulp environment into a regenerative niche. Teeth, it turns out, may know how to heal themselves—we just needed to learn the language they use to ask for help.

Subject of Research: Fibronectin-mediated macrophage–stromal cell crosstalk driving angiogenesis and regeneration of the dental pulp–dentin complex

Article Title: Fibronectin-guided immune–stromal cell crosstalk promotes angiogenesis in pulp–dentin complex regeneration

Article References: Jeong, S., Park, S. Y., Ku, H., Eom, B. S., Kim, D., & Kim, J. M. (2026). Fibronectin-guided immune–stromal cell crosstalk promotes angiogenesis in pulp–dentin complex regeneration. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01863-4

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01863-4

Keywords: fibronectin, macrophages, dental pulp stem cells, angiogenesis, dental caries, pulp revascularization, extracellular matrix, integrins, regenerative dentistry, NF-kappa-B, chemokines, tissue regeneration

SPP1 is a secreted glycosylated phosphoprotein with a long-established resume in skeletal biology, where it participates in bone mineralization and the remodeling of the extracellular matrix. But in tumors, the same molecule takes on a darker role. The review synthesizes evidence showing that SPP1 is produced by multiple players within the tumor microenvironment, including tumor cells themselves, tumor-associated macrophages and cancer-associated fibroblasts. Once secreted, it signals through a family of cell-surface receptors, chiefly integrins that recognize its arginine-glycine-aspartic acid motif, as well as variants of the CD44 receptor. Through these interactions, SPP1 transmits instructions that reshape how immune cells behave, how they move through tissue, and whether they can reach the tumor at all.

One of the most consequential effects of SPP1 signaling is its influence on macrophages, the versatile immune cells that populate nearly every tumor. The review describes how SPP1 drives the polarization of tumor-associated macrophages toward a pro-tumor phenotype, a state in which these cells abandon their immune-surveillance duties and instead support tumor growth, angiogenesis and tissue remodeling. Single-cell RNA sequencing studies, which allow researchers to profile gene expression in individual cells, have repeatedly identified distinct populations of SPP1-positive macrophages in human tumors, and these cells are consistently associated with poor clinical outcomes. Rather than simply being bystanders, these macrophages appear to be active architects of an immunosuppressive environment, secreting SPP1 that reinforces their own suppressive identity and that of their neighbors.

The consequences extend well beyond macrophages. According to the review, SPP1 impairs the function of innate immune cells, the rapid-response arm of the immune system that includes natural killer cells and dendritic cells. It also induces the exclusion and exhaustion of T cells, the cytotoxic lymphocytes that immunotherapies such as immune checkpoint inhibitors are designed to unleash. T cell exhaustion is a state of progressive dysfunction in which T cells lose their ability to kill tumor cells, and SPP1 appears to promote this process while simultaneously building physical barriers that keep T cells away from tumor cells in the first place. By remodeling the extracellular matrix, the fibrous scaffold that permeates tumors, SPP1 helps create a form of immune exclusion in which anti-tumor lymphocytes linger at the tumor margin, unable to penetrate the tumor core.

This combination of effects helps explain why many patients fail to respond to immune checkpoint inhibitors, the blockbuster therapies that block inhibitory receptors such as PD-1 and have transformed the treatment of melanoma, lung cancer and other malignancies. Checkpoint inhibitors work best in tumors that are already infiltrated by T cells, so-called hot tumors. SPP1-rich tumors, by contrast, tend to be cold, lacking meaningful lymphocyte infiltration and exhibiting dense, suppressive stroma. The review positions the SPP1 axis as a promising therapeutic target precisely because it operates upstream of these failures: neutralizing SPP1 or blocking its receptors could convert a cold, excluded tumor into one that immune therapies can actually reach.

Encouragingly, the review catalogs a growing arsenal of strategies aimed at doing exactly that. Direct SPP1 neutralization, using antibodies or other decoy molecules, aims to mop up the protein before it reaches its receptors. Receptor blockade seeks to sever the downstream signaling that integrins and CD44 variants transmit into immune and stromal cells. A third approach targets the source: depleting or reprogramming the SPP1-positive tumor-associated macrophages that manufacture much of the tumor’s supply. Each strategy attacks a different node of the axis, and the review suggests that combining them with existing modalities may be where the greatest potential lies.

Those combination possibilities are particularly striking. The authors describe evidence supporting the pairing of SPP1 targeting with immune checkpoint inhibitors, with agonists of the STING pathway, a innate immune sensor that when activated can ignite anti-tumor inflammation, with cytokine-based therapies, and with conventional treatments such as radiotherapy and chemotherapy. The logic is complementary: SPP1 blockade dismantles the immunosuppressive and exclusionary architecture of the tumor, while the partner therapy supplies or amplifies the immune attack. Radiotherapy and chemotherapy, for their part, can release tumor antigens and induce immunogenic cell death, effects that SPP1 targeting may help convert into durable systemic immunity rather than transient local responses.

Drug delivery innovation is also entering the picture. The review highlights work on lipid nanoparticles, the same lipid-based vehicles that proved their worth in mRNA vaccines, engineered to deliver SPP1-targeting small interfering RNA into tumors. One described design uses mannosylated nanoparticles, decorated with sugar molecules that guide them toward macrophages, to deliver SPP1 siRNA in combination with interferon-gamma, a cytokine that can push macrophages back toward an anti-tumor state. Such approaches illustrate how the field is moving beyond simple antibody blockade toward precision tools that can reprogram specific cell populations within the tumor microenvironment, potentially resetting the balance between suppression and immunity at its source.

Yet the review is careful to temper enthusiasm with a sober accounting of the translational challenges ahead. SPP1 signaling is context-dependent: the same molecule can exert different, sometimes opposing, effects depending on the receptor engaged, the cell type targeted and the stage of tumor progression. Osteopontin has documented roles in normal wound healing and tissue homeostasis, raising the possibility that systemic blockade could interfere with beneficial biology. The authors also emphasize the need for biomarker development and patient stratification, since identifying which patients harbor SPP1-driven, immune-excluded tumors will be essential for selecting who benefits from SPP1-directed therapies and for designing clinical trials capable of demonstrating meaningful benefit.

The broader message of the review is that the tumor microenvironment is not a passive backdrop but an actively engineered landscape, and SPP1 is one of its chief engineers. By promoting pro-tumor macrophage polarization, disabling innate immunity, exhausting and excluding T cells, and hardening the extracellular matrix into a physical barrier, SPP1 sits at a convergence point of nearly every mechanism tumors use to hide from the immune system. The authors conclude that targeting the SPP1 axis offers a promising strategy for remodeling the tumor microenvironment and enhancing antitumor immunity, a conclusion that is likely to accelerate preclinical and clinical efforts. If those efforts succeed, a molecule named for its abundance in bone may become one of the most important levers for turning immunologically cold tumors into ones that modern immunotherapy can finally heat up.

Subject of Research: The role of secreted phosphoprotein 1 (SPP1) in regulating immunosuppression in the tumor microenvironment and therapeutic strategies targeting the SPP1 axis

Article Title: Reprogramming the tumor immune landscape through SPP1 targeting

Article References: Gao, L., Yang, J., & Teng, Y. (2026). Reprogramming the tumor immune landscape through SPP1 targeting. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03844-x

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03844-x

Keywords: SPP1, osteopontin, tumor microenvironment, tumor-associated macrophages, cancer-associated fibroblasts, immune evasion, T cell exclusion, immune checkpoint inhibitors, CD44, integrins, lipid nanoparticles, cancer immunotherapy

Integrins are heterodimeric adhesion receptors composed of an alpha and a beta chain, and they sit embedded in cell membranes across virtually all metazoan life. Their job is deceptively simple but biologically profound: they anchor cells to the extracellular matrix, transmit mechanical forces, and relay chemical signals from outside the cell to the interior. In humans, integrins are implicated in everything from wound healing to cancer metastasis, and they have become prized pharmaceutical targets. In parasitic helminths, however, integrin homologues have been identified at the sequence level for years, yet their three-dimensional organization and ligand-binding behavior remained largely uncharted territory. The new study set out to close that gap using an integrative computational pipeline rather than laboratory experiments alone.

The researchers began with comparative sequence analysis across medically important Schistosoma species, searching for conserved integrin genes in the genomes of the parasites. Their screen revealed a striking asymmetry. On the beta side, a single highly conserved orthologue, which they named Smβ1, was present and well preserved across species, suggesting that it performs an essential function that evolution has been reluctant to alter. On the alpha side, the picture was more complicated: four divergent alpha-integrin subunits were identified, each carrying distinctive sequence features that hinted at different evolutionary histories and potentially different binding partners. This combination of one conserved beta chain and several variable alpha chains mirrors the architecture of integrin systems in other organisms, where the beta subunit provides the core ligand-binding machinery and the alpha subunit tunes its specificity.

To move from sequences to structures, the team deployed three independent protein-structure prediction engines: AlphaFold3, RoseTTAFold and trRosetta. Convergent predictions from these tools showed that the betaI-containing region of Smβ1 retains the characteristic integrin fold that has been described in exquisite detail for human receptors. Critically, the model preserved the three canonical metal-coordination sites that define integrin ligand recognition: the metal-ion-dependent adhesion site, known as MIDAS, which directly coordinates the acidic residue of incoming ligands; the adjacent ADMIDAS site, which allosterically regulates the receptor’s activation state; and the synergistic metal-binding site, or SyMBS, which helps stabilize the ligand-bound conformation. The retention of these features in a parasite receptor is significant because it suggests that the fundamental chemistry of integrin-ligand engagement, dependent on metal ions bridging receptor and ligand, has been conserved across hundreds of millions of years of evolution separating flatworms from vertebrates.

With individual subunit structures in hand, the next challenge was determining which alpha chain pairs with Smβ1. Integrin function depends entirely on the correct heterodimer assembly, and predicting which of the four candidate alpha subunits forms a stable, functional complex with the beta chain is a problem that sequence similarity alone cannot solve. The researchers therefore constructed an integrated structural benchmarking framework that scored each candidate assembly across multiple independent dimensions: conservation of the overall fold, stereochemical and backbone quality of the predicted model, VoroMQA-based assessment of Voronoi packing density, the architecture of the alpha-beta interface itself, the buried surface area at the interface, and separate interface-context analyses designed to catch artifacts that single metrics might miss.

When the scores were tallied, one pairing stood out. Smα1 in combination with Smβ1 was ranked as the leading heterodimer candidate, while Smα3 paired with Smβ1 remained a structurally plausible alternative that could not be excluded. This ranking mattered because the identity of the alpha subunit shapes the geometry of the ligand-binding pocket that forms at the interface between the two chains. The team then subjected both candidate assemblies to ligand-challenge modelling, docking RGD-containing peptides into the predicted binding sites and comparing the resulting interaction geometries against a human α5β1 integrin benchmark whose RGD-bound structure is experimentally established.

The results were revealing. Smα1/Smβ1 more readily reproduced the coupled interaction pattern seen in the human benchmark, in which the arginine residue of the RGD motif anchors to a defined pocket on the alpha subunit while the aspartate residue coordinates the MIDAS metal ion on the beta subunit. Smα3/Smβ1, by contrast, was less consistent in reproducing this canonical geometry. Across expanded ensembles of ligand structures, canonical and cyclic RGD-containing peptides preferentially adopted RGD-like interaction geometries with the receptor, whereas an RGE mutant peptide, in which the aspartate is replaced by glutamate, and various non-RGD control peptides showed reduced or absent canonical interaction features. This specificity pattern is exactly what one would expect from a genuine RGD-recognizing integrin, since the RGE substitution is a classic experimental control that abolishes integrin binding in well-characterized systems.

Molecular dynamics simulations provided the temporal dimension that static docking cannot capture. In trajectories running 100 and 200 nanoseconds, the canonical RGD peptide remained within a comparatively restricted conformational regime associated with the receptor, suggesting a stable engagement, while the RGE mutant underwent greater displacement and induced more structural mobility in the contact site. Complementary MM/GBSA energetic analysis computed over the 200-nanosecond trajectory frames further supported more favourable energetic compatibility for RGD than for RGE. Together, these dynamic and energetic measures reinforce the picture painted by the docking experiments: the Smα1/Smβ1 complex behaves, under modelled conditions, like a receptor that genuinely prefers RGD ligands over near-identical decoys.

Beyond ligand binding, the study ventured into signaling territory with an exploratory network analysis using the STRING database. This placed Smβ1 within a predicted adhesome-like network that includes the integrin-linked kinase, or ILK, together with its PINCH and Parvin partners and kinase-associated components. In animal cells, the ILK-PINCH-Parvin complex is a central scaffold of the integrin adhesion complex, coupling receptors at the membrane to the actin cytoskeleton and to signaling pathways. Finding a predicted network of this composition around a schistosome beta integrin raises the possibility that the parasite uses signaling machinery broadly analogous to that of its host, which carries implications for how the worm adheres to and navigates host tissues during its complex life cycle.

The authors are careful to frame their conclusions as hypothesis-generating rather than definitive. Every result in the study derives from computational prediction and simulation, and the models, however sophisticated, remain subject to experimental validation. The paper explicitly presents its findings as experimentally testable hypotheses concerning alpha-beta pairing, metal-dependent ligand recognition and integrin-associated signaling in schistosomes. Still, the implications are considerable. If Smα1/Smβ1 is confirmed as a functional RGD-recognizing receptor, it would open a new window on how S. mansoni interacts with host extracellular matrix during infection, and it would offer a structurally characterized parasite-specific target whose human counterparts are already druggable, potentially accelerating the search for much-needed new therapies against a disease for which treatment still relies almost entirely on a single drug, praziquantel.

Subject of Research: Structural and ligand-binding characterization of Schistosoma mansoni integrin receptors

Article Title: Computational structural analysis of Schistosoma integrins supports Smα1/Smβ1 as an RGD-compatible receptor candidate

Article References: Adu, E. A., Owoloye, A., Shakela, N., Aziz, R. N., Boakye, A. O., Acheampong, E., Nyarko, E. N. Y., Adu-Amoah, L., Afum-Adjei Awuah, A., Amuasi, J. H., & Obirikorang, C. (2026). Computational structural analysis of Schistosoma integrins supports Smα1/Smβ1 as an RGD-compatible receptor candidate. BMC Genomics. https://doi.org/10.1186/s12864-026-13429-9

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13429-9

Keywords: Schistosoma mansoni, schistosomiasis, integrins, Smβ1, Smα1, RGD motif, AlphaFold3, molecular dynamics, MIDAS, protein-ligand interactions, host-parasite interactions, structural genomics

The authors frame their argument around the matrisome, a term describing the complete inventory of ECM proteins and associated molecules in a tissue. First defined computationally and then characterised experimentally by proteomics in 2012, the matrisome encompasses core structural components such as collagens, laminins, fibronectin and proteoglycans, together with matrix-remodelling enzymes, growth factors and cross-linking proteins. Because the matrix is abundant, accessible and often tumour-specific in its composition, the review positions it as an appealing reservoir of biomarkers and therapeutic targets. Yet the authors are candid about the field’s troubled history: early attempts to drug the matrix in patients with cancer, most notably broad-spectrum matrix metalloproteinase inhibitors and the integrin antagonist cilengitide, failed to deliver clinical benefit, a legacy that shaped scepticism toward matrix-directed oncology for years.

What has changed, according to the review, is a convergence of technology and fundamental biology. Novel proteomic methods now allow researchers to catalogue the composition of tumour matrices with unprecedented depth, while advanced imaging approaches reveal the physical and mechanical properties of the matrix in three dimensions. Single-cell RNA sequencing and spatial transcriptomics map which cells in the tumour microenvironment produce and remodel matrix components, and computational tools such as MatriCom infer cell–matrix interactions directly from sequencing data. Resources like MatrisomeDB 2.0 consolidate this knowledge into searchable databases. Together, these methods have transformed the matrix from a poorly characterised background into a quantifiable, dynamic system whose alterations can be tracked during tumour progression and treatment.

Central to the review’s argument is the recognition that matrix remodelling is not merely a consequence of tumour growth but a driver of it. Cancer-associated fibroblasts, the most abundant stromal cells in many solid tumours, deposit and stiffen the matrix, generating a desmoplastic environment that is characteristic of aggressive malignancies such as pancreatic ductal adenocarcinoma. The mechanical properties of this remodeled matrix matter as much as its composition. Increased stiffness promotes epithelial–mesenchymal transition, invasion and chemoresistance, while aligned collagen fibres provide highways along which cancer cells migrate toward blood vessels. Viscoelasticity, compressive stresses and fibre architecture all feed into mechanotransduction pathways, largely through integrins and discoidin domain receptors, that reprogramme cell behaviour in ways that favour malignancy.

The matrix also exerts profound control over the immune system, a dimension with immediate clinical relevance. Dense, stiff, cross-linked stroma can physically exclude T cells from tumours, restrict their migration and suppress their function. Collagen density has been shown to regulate the activity of tumour-infiltrating T cells and the immunosuppressive behaviour of macrophages, while matrix proteins such as tenascin-C can immobilise infiltrating lymphocytes through chemokine sequestration. These findings help explain why fibrotic, matrix-rich tumours often respond poorly to immune checkpoint inhibitors, and they suggest that normalising the matrix could be a route to sensitising otherwise immunologically cold tumours to immunotherapy.

On the diagnostic front, the review details how matrix properties are already being leveraged in the clinic. Mammographic density, which reflects stromal collagen and proteoglycan content, is a well-established risk factor for breast cancer. Shear-wave elastography measures tumour stiffness non-invasively and correlates with breast cancer subtypes and hepatocellular carcinoma diagnosis. Second harmonic generation microscopy quantifies collagen fibre alignment in biopsy specimens, where tumour-associated collagen signatures carry prognostic weight. Matrisome-derived gene signatures predict outcome in breast, lung and other cancers, and serum fragments of collagens and other matrix proteins are being evaluated as blood-based biomarkers of desmoplasia and survival. Collagen-targeted molecular MRI and PET tracers are extending matrix imaging from the microscope to whole-body clinical imaging.

Therapeutically, the review organises emerging strategies into three broad categories. The first uses tumour-specific matrix components as anchors for targeted delivery. Splice variants of fibronectin and tenascin-C that are absent from normal adult tissues but abundant in tumour stroma have been exploited by antibodies, immunocytokines and antibody–drug conjugates designed to concentrate payloads within the tumour. Collagen-binding formulations of interleukin-12 and checkpoint inhibitors aim to localise immunostimulatory drugs at the tumour site while limiting systemic toxicity, and integrin-targeting agents such as sigvotatug vedotin are advancing through clinical trials in lung cancer.

The second category, which the authors call matritherapies, seeks to normalise the tumour matrix rather than destroy it. Lessons from failed hyaluronidase trials have been refined into biomarker-selected approaches, with pegvorhyaluronidase alfa showing benefit in hyaluronan-high pancreatic cancer in a phase III setting. Pan-lysyl oxidase inhibitors, designed to block collagen cross-linking and stromal stiffening, have enhanced chemotherapy response in preclinical pancreatic cancer models and are entering clinical testing. Repurposed antifibrotic drugs such as losartan, pirfenidone and nintedanib are being evaluated for their ability to decompress tumour vessels, reduce collagen deposition and improve drug delivery, while oncolytic adenoviruses engineered to express hyaluronidase are being tested for their stroma-disrupting effects.

The third strategy targets matrix-dependent signalling. Integrin inhibitors, discoidin domain receptor 1 antibodies that disrupt collagen fibre alignment and reverse immune exclusion, and focal adhesion kinase inhibitors such as defactinib represent attempts to sever the mechanotransductive links between the matrix and malignant cell behaviour. Blocking transforming growth factor-β, a central mediator of fibrosis and immune suppression, has shown the capacity to convert T-cell-excluded tumours into inflamed ones responsive to checkpoint blockade. The review emphasises that combination approaches, pairing matrix normalisation with chemotherapy, radiotherapy or immunotherapy, are likely to be more successful than matrix targeting alone, reflecting the lesson learned from earlier monotherapy failures.

The authors conclude that the tumour matrisome has moved decisively from the margins of cancer biology to its centre. With validated prognostic signatures, imaging biomarkers in clinical use and a growing pipeline of matrix-directed therapeutics, the extracellular matrix is no longer an obstacle to treatment but a target in its own right. The challenge ahead, they argue, is precision: identifying which matrix alterations in which tumour contexts warrant intervention, and designing trials that select patients on the basis of matrix biology rather than treating the stroma as a uniform entity. If that precision can be achieved, the scaffolding that tumours build to support themselves may become the very structure that brings about their downfall.

Subject of Research: The composition, signalling functions and therapeutic targeting of the tumour extracellular matrix (matrisome) in cancer

Article Title: Understanding and targeting the tumour matrisome

Article References: Pally, D., Englund, J. I., & Naba, A. (2026). Understanding and targeting the tumour matrisome. Nature Reviews Clinical Oncology. https://doi.org/10.1038/s41571-026-01203-5

Image Credits: AI Generated

DOI: 10.1038/s41571-026-01203-5

Keywords: tumour matrisome, extracellular matrix, cancer-associated fibroblasts, matrix remodelling, mechanotransduction, collagen, integrins, matritherapies, tumour microenvironment, biomarkers, immunotherapy resistance, drug delivery

The review begins with the fundamental biomechanics of the organ. During filling, the bladder wall must expand dramatically while keeping internal pressures low, a property known as high compliance that depends on the viscoelastic behavior of its layered structure: a barrier-forming urothelium, a collagen-rich lamina propria and the detrusor smooth muscle. Classical studies dating back to the 1970s established that the bladder wall exhibits time-dependent, viscoelastic responses to loading, with passive properties governed largely by collagen and elastin in the extracellular matrix and active properties determined by smooth muscle tone. During voiding, coordinated detrusor contraction generates the pressures needed to expel urine, while urine flow itself imposes shear stress on the urothelial surface. Each fill-void cycle therefore exposes bladder cells to repeated, rhythmic deformation, and the review emphasizes that this mechanical rhythm is not merely background noise but a regulatory signal that shapes organ development, sensation and repair throughout life.

How do bladder cells actually detect these forces? The authors catalog an expanding arsenal of mechanosensors. Chief among them are mechanosensitive ion channels, most notably the Piezo family. PIEZO2 in sensory neurons and urothelial cells has been shown to coordinate the urination reflex, while PIEZO1 in the urothelium mediates stretch-evoked calcium influx and ATP release, and its expression rises after partial bladder outlet obstruction. Transient receptor potential channels, including TRPV1, TRPV4, TRPM3 and TRPM8, contribute to stretch sensing, inflammation-associated hypersensitivity and afferent signaling, and several TRP-targeted drugs are already in clinical development for bladder disorders. Beyond ion channels, the review highlights integrins, the transmembrane receptors that link cells to the extracellular matrix and transmit force through focal adhesion kinase; muscarinic acetylcholine receptors, which modulate stretch-induced responses in the urothelium and smooth muscle; and purinergic receptors, which sense the ATP released mechanically from urothelial cells and translate it into afferent nerve activation and detrusor responses.

Downstream of these sensors lies the machinery of mechanotransduction, the intracellular pathways that convert mechanical cues into biochemical decisions. The review details how physiological stretch activates integrin-FAK signaling to drive controlled proliferation of urothelial and smooth muscle cells, supporting tissue maintenance and wound healing, while hydrostatic pressure stimulates DNA synthesis through PI3K/Akt pathways. The Hippo-YAP/TAZ axis emerges as a central hub: mechanical strain and matrix stiffness promote nuclear translocation of YAP, which cooperates with Smad3 to drive pathological smooth muscle proliferation in fibrosis progression. Rho GTPase signaling, actomyosin contractility and ERK1/2 pathways further link force sensing to gene expression, extracellular matrix synthesis and cell fate. In health, these pathways maintain homeostasis; in disease, their dysregulation becomes a driver of injury.

The pathological consequences of mechanical overload are illustrated most vividly by bladder outlet obstruction, a condition commonly caused by benign prostatic hyperplasia. Obstruction elevates both stretch forces and hydrostatic pressures during storage and voiding, and the review traces the resulting cascade: urothelial dysfunction and barrier disruption, release of inflammatory mediators and ATP, recruitment and polarization of macrophages, mast cell activation, and a progressive transition from inflammation to fibrosis. Elevated pressures have been shown to activate Piezo1 and exacerbate bladder fibrosis, while PIEZO2 is downregulated in the detrusor of men with obstruction, correlating with urinary retention and reduced compliance. Fibrotic remodeling stiffens the bladder wall, and this increased matrix stiffness feeds back through mechanosensitive pathways, including YAP/Smad3 signaling, to perpetuate smooth muscle proliferation and further stiffening, a vicious cycle the authors describe as biomechanical memory embedded in the tissue.

Inflammation and immunity are also framed in mechanical terms. Recent work shows that Piezo1 modulates macrophage polarization and stiffness sensing, that YAP-mediated mechanotransduction tunes the macrophage inflammatory response, and that mechanical communication between fibroblasts, immune cells and smooth muscle orchestrates fibrosis progression. The review argues that mechanotransduction is not confined to structural cells but extends to the immune compartment, positioning mechanical cues as regulators of the inflammatory milieu that determines whether an injured bladder heals or scars. Epithelial-mesenchymal transition, in which urothelial cells acquire fibroblast-like, collagen-producing phenotypes, is likewise promoted by elevated storage and voiding pressure cycles and by TGF-beta signaling intertwined with Rho kinase pathways.

On the therapeutic front, the review is cautiously optimistic but candid about the early stage of the field. Existing drugs already intersect with mechanosensitive biology: antimuscarinics reduce stretch-evoked ATP release from the bladder mucosa, TRP channel antagonists such as TRPM8 blockers and TRPV1-targeting agents show efficacy in overactive bladder and pain models, and purinergic P2X3 antagonists like gefapixant, approved for chronic cough, exemplify the druggability of mechanosensory receptors. Novel agents are pushing further, including bladder-selective M3 antagonists, M3 positive allosteric modulators for underactive bladder, and Piezo1 modulators ranging from the activator Yoda1 to inhibitors such as GsMTx4. Preclinical studies suggest that targeting Piezo1, integrin pathways or YAP signaling can mitigate obstruction-induced and neurogenic bladder fibrosis, and even tetrahedral framework nucleic acids have shown antifibrotic effects by modulating macrophage polarization. Yet the authors stress that no mechanotransduction-targeted therapy has yet been validated specifically for bladder injury, and that drugs aimed at mechanosensitive ion channels and integrins represent the most promising frontier for future investigation.

Beyond pharmacology, the review points to engineering approaches that could reshape bladder repair. Biomechanical modeling with four-dimensional reconstruction of bladder filling, computational fluid dynamics of urethral flow, and flexible implantable sensors for pressure monitoring are refining how researchers quantify the organ’s mechanical environment. Regenerative medicine strategies, including bladder acellular matrix scaffolds, must account for the fact that scaffold stiffness and architecture directly influence cell behavior through the same mechanotransduction pathways the review describes. Urinary ATP is emerging as a dynamic biomarker of detrusor overactivity and interstitial cystitis severity, offering a translational readout of mechanosensory activity that could guide diagnosis and treatment monitoring.

The overarching message is a reframing of bladder disease as, in substantial part, a mechanobiological disorder. Abnormal mechanical environments are both indicators and drivers of bladder pathology, and understanding the differential mechanosensation and transduction pathways that distinguish physiological adaptation from pathological remodeling is essential for developing therapies that promote genuine repair rather than symptomatic suppression. As the population ages and conditions such as benign prostatic hyperplasia, overactive bladder and neurogenic bladder dysfunction grow more prevalent, the mechanobiology of the bladder may prove to be one of urology’s most consequential frontiers, transforming how clinicians think about an organ they have long treated primarily as a plumbing problem.

Subject of Research: Biomechanical regulation of bladder injury and repair through mechanosensors and mechanotransduction pathways

Article Title: Biomechanical regulation of bladder injury and repair

Article References: Chen, J., Chen, Y., Di, X., Zeng, X., Shen, S., Lin, L., Li, Y., Liao, B., Shen, H., Peng, L., Jin, T., & Luo, D. (2026). Biomechanical regulation of bladder injury and repair. Nature Reviews Urology. https://doi.org/10.1038/s41585-026-01185-0

Image Credits: AI Generated

DOI: 10.1038/s41585-026-01185-0

Keywords: bladder, mechanotransduction, Piezo1, bladder outlet obstruction, fibrosis, urothelium, mechanosensitive ion channels, integrins, TRP channels, purinergic signaling, overactive bladder, YAP signaling