Extracellular Matrix Stiffness Regulates Mechanical–Metabolic Coupling in Tumors: Mechanisms and Therapeutic Opportunities

The extracellular matrix (ECM) stiffening in the tumor microenvironment (TME) is an important physical characteristic of solid tumors and can serve as an active signaling hub that regulates the biological behavior of tumors. Abnormal deposition, cross-linking, and remodeling of collagen not only alter the mechanical properties and structure of tissues but also convert mechanical stimuli into intracellular signals through mechanosensitive ion channels such as integrin-FAK, Hippo-YAP/TAZ, Piezo1/2, and Transient receptor potential vanilloid subtype 4 (TRPV4), thereby reprogramming tumor cell metabolism, including enhancing the Warburg effect, lipid synthesis, and glutamine catabolism, forming a malignant cycle of “matrix stiffening - metabolic reprogramming” that promotes tumor progression and treatment tolerance. Mechanical signals can also create an immunosuppressive TME by restricting CD8 ⁺ T-cell infiltration and promoting tumor-associated macrophage polarization toward an M2-like state. Metabolites generated by reprogrammed cells, including lactate, can further remodel and stiffen the ECM, creating a positive-feedback loop. Genetic and epigenetic heterogeneity, hypoxia, nutrient availability, and oncogenic signaling may uncouple mechanical regulation from metabolic output and complicate therapeutic targeting. Non-coding RNAs (ncRNAs) add a regulatory layer that may connect mechanotransduction with metabolic plasticity and immune remodeling, although their effects remain context dependent. This review integrates the existing evidence on the regulation of tumor metabolism and immune microenvironment by ECM mechanical signals, focuses on summarizing the key mechanical sensing pathways, feedback mechanisms, and therapeutic targets, and proposes research directions for precisely identifying key regulatory nodes of the mechanical-metabolic axis by combining spatial omics, metabolic flux analysis, and mechanical imaging techniques, providing a conceptual framework for developing novel therapeutic strategies targeting the biomechanical processes of tumors.