Biomechanics of the tumor extracellular matrix and regulatory T cells: regulatory mechanisms and potential therapeutic targets

Abstract

Tumor-infiltrating regulatory T cells (TI-Tregs) are characterized by their abnormal accumulation and heightened immunosuppressive activity. However, the biomechanical mechanisms that govern Treg identity and function through extracellular matrix (ECM) properties remain poorly understood. In three-dimensional culture systems and the tumor microenvironment (TME), increased matrix stiffness and viscoelasticity have been shown to promote Treg differentiation and expansion. Structural remodeling of the ECM, particularly the realignment of collagen fibers and the reduction in effective pore size, significantly enhances Treg migration. Moreover, biomechanical signals derived from the ECM strengthen the oxidative phosphorylation (OXPHOS) metabolic phenotype and immunosuppressive function of Tregs by modulating mitochondrial dynamics. This review provides a comprehensive analysis of the molecular events through which ECM mechanical properties-such as stiffness, viscoelasticity, and topological structure-regulate Treg identity and functionality, as well as the mechanical sensing and response mechanisms employed by Tregs. The potential for targeting Treg mechanosensors and mechanotransduction pathways to develop mechano-immunomodulatory strategies for cancer therapy is also discussed.

Keywords: Biomechanics; Extracellular matrix; Regulatory T cells; Stiffness; Viscoelasticity.

Fig. 1

The biomechanical properties of tumor ECM. a Stiffness: Aberrant CAF activation disrupts the balance between MMPs and TIMPs (i). The vicious cycle of mechanical signals critically drives the increase in matrix stiffness within the TME (ii). b Viscoelasticity: The two hallmark phenomena of viscoelastic materials: stress relaxation test, creep test (i). The viscoelasticity of biomaterials can be modified by crosslinking strength and polymer chain molecular weight(ii). c Topology, also referred to as matrix structure: Anisotropic alignment of collagen fibers (i). Reduced effective porosity (ii). Increased surface roughness (iii). CAFs, Cancer-associated fibroblasts; MMPs, Matrix metalloproteinases; TIMPs, Tissue inhibitors of metalloproteinases; LOX, Lysyl oxidase. Figures created with BioRender.com

Fig. 2

Effects of ECM mechanical properties on the differentiation, infiltration, and migration of Tregs. DDR1, Discoidin domain receptor 1; FAK, Focal adhesion kinase; Src, Src-family kinases; ICAM-1: Intercellular adhesion molecule-1; AP-1, Activator Protein 1; Figures were created with BioRender.com

Fig. 3

Effect of ECM mechanical properties on the metabolism and function of Tregs. HIF-1α, Hypoxia-inducible factor-1 alpha; OXPHOS, Oxidative phosphorylation; FAO, Fatty acid oxidation; Lars2: Leucyl-tRNA synthetase; OPN, Osteopontin; MIEF1: Mitochondrial elongation factor 1; DRP1: Dynamin-related protein 1. Figures were created with BioRender.com