Tumour Matrisome Emerges as a Rich Source of Cancer Biomarkers and Drug Targets

The space between cancer cells has long been treated as biological scaffolding, a passive framework that simply holds a tumour together. A comprehensive review published in Nature Reviews Clinical Oncology argues that this view is badly out of date. Written by Dharma Pally and Alexandra Naba of the University of Illinois Chicago together with Johanna I. Englund of the University of Helsinki, the review synthesises a decade of progress showing that the extracellular matrix, or ECM, is an active participant in nearly every stage of tumour development. Far from being inert packing material, the matrix transmits mechanical and biochemical signals that govern whether cancer cells proliferate, survive, migrate or lie dormant, and its accumulation is now recognised as a hallmark of cancer that correlates with aggressiveness and survival across tumour types.

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