Matrix Viscoelasticity: The Overlooked Architect of Solid Tumour Evolution

With advances in measurement technologies and the growing demand for precision oncology, viscoelasticity has moved from a peripheral mechanical parameter—once overshadowed by stiffness—to the centre of tumour mechanobiology. This shift has begun to reveal how mechanical properties govern the initiation and progression of solid tumours that do not exhibit pronounced stiffening and has offered fresh insights into the behaviour of several rare cancers. Recent work on matrix viscoelasticity has largely focused on hepatocellular carcinoma, breast cancer, pancreatic cancer and gliomas, with additional observations in rarer entities such as osteosarcoma. In our recent review, we discussed the relationship between matrix viscoelasticity and tumour development and noted that viscoelasticity, once decoupled from stiffness, can independently shape tumour initiation and progression. It modulates endothelial-mesenchymal transition, proliferation, invasion, migration, stemness maintenance, the establishment of an immunosuppressive microenvironment, angiogenesis and metabolic reprogramming. These effects are strongly cancer-type-dependent, and the response patterns display marked heterogeneity [1]. Such wide-ranging influences rely on how tumour cells and other components of the tumour microenvironment (TME), such as cancer-associated fibroblasts, sense and respond to viscoelasticity. Mechanosensing of viscoelastic cues has been tightly linked to YAP/TAZ signalling [2] and Piezo channels [3]. Tumour cells further adapt to the mechanical properties of the TME by reprogramming their metabolism to remodel the cytoskeleton, thereby acquiring fitness in a mechanically specialised niche. Therapeutic strategies that target the mechanical properties of the TME are therefore appealing. However, most current attempts to remodel the niche that sustains solid tumours have focused on softening the matrix—that is, altering stiffness. Viscoelasticity itself is tunable. A key determinant is the heterogeneity of collagen within the TME, and advanced glycation end-products have recently been shown to play an important part in hepatocarcinogenesis in the pre-cirrhotic liver [4]. Another key determinant is the abundance and molecular-weight distribution of hyaluronan. Hyaluronan underlies a distinct manifestation of viscoelasticity—poroelasticity—by governing fluid flow through a highly hydrated matrix, a property that is indispensable in pancreatic ductal adenocarcinoma [5]. Through its actions on, and feedback from, different cellular and acellular constituents, viscoelasticity helps weave a complex interaction network within the TME. Viscoelastic cues can remodel stromal components and thereby indirectly influence tumour-cell behaviour. For example, in pancreatic ductal adenocarcinoma, increased matrix viscoelasticity promotes the spreading and activation of cancer-associated fibroblasts, enhancing their paracrine signalling and via cytokine release, fostering invasive tumour phenotypes [6]. In return, TME components actively reshape the mechanical landscape: matrix metalloproteinases constitute one of the principal routes by which tumour cells reconfigure matrix viscoelasticity over time [7]. Crucially, viscoelasticity should not be regarded as relevant only in solid tumours that lack marked stiffening. Studies have shown that mice with higher baseline liver viscoelasticity exhibit greater susceptibility to hepatocellular carcinoma, suggesting that viscoelasticity may increase tumour predisposition at the very early stages of tumorigenesis. This observation again underscores the importance of early lifestyle modification and timely clinical interventions in chronic liver disease and cirrhosis [8]. Viewing solid tumours through the new mechanical lens of matrix viscoelasticity is still at an early stage. The dominant role of stiffness in clinical MRI and ultrasound, together with the complexity of viscoelastic modelling, has led to the relative neglect of viscoelasticity, which arguably better reflects the in vivo TME. Many questions remain. Are there dedicated sensors that couple viscoelasticity to specific tumour behaviours? Can matrix viscoelasticity serve as a mechanical label that supports new schemes of tumour classification and risk stratification? Does it harbour genuine translational potential as a target for drug development? Addressing these outstanding issues will require concerted basic research and well-designed clinical cohort studies. Recent work suggests that the relationship between matrix viscoelasticity and stiffness is at once dependent, independent, and cooperative. Viscoelasticity requires a certain level of stiffness to manifest, yet decoupled viscoelasticity can act as an independent driver of solid-tumour progression and complement stiffness as a mechanical signal. We look forward to Organ Medicine serving as a bridge between basic and clinical research on viscoelasticity, helping to translate this emerging mechanical perspective into tangible benefits for patients. Ruixi Huang: writing – original draft. Yupeng Guan: conceptualization, writing – original draft, writing – review and editing. The authors have nothing to report. The authors received no specific funding for this work. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report.