Matrix stiffness in tumor immune evasion and immunotherapy resistance: from mechanotransduction to therapeutic intervention

The tumor microenvironment is characterized not only by biochemical alterations but also by profound biophysical abnormalities, among which increased extracellular matrix (ECM) stiffness represents a defining hallmark of solid malignancies. Once regarded as a passive structural consequence of desmoplasia, matrix stiffness is now recognized as an active, master regulator of anti-tumor immunity. This review synthesizes current understanding of how elevated matrix stiffness orchestrates immune suppression through interconnected biophysical and biochemical mechanisms. We delineate the biophysical basis of tumor stiffening driven by enhanced collagen deposition, lysyl oxidase-mediated crosslinking, and cancer-associated fibroblast activation. We systematically examine how stiff matrices reshape innate immunity, emphasizing that macrophage polarization is context-dependent: M2-like immunosuppressive phenotypes predominate in the stiff tumor stroma, whereas defined biomaterial substrates can prime inflammatory states. We also cover the metabolic reprogramming of tumor-associated macrophages that depletes arginine while secreting immunosuppressive ornithine, as well as altered dendritic cell maturation and function. We then discuss how stiff matrices suppress adaptive immunity by physically impeding T lymphocyte migration, actively inducing CD8 + T cell terminal exhaustion through the recently discovered Piezo1/Ca² + /CaMKII/CREB/Osr2 biomechanical checkpoint, promoting regulatory T cell (Treg) differentiation, and upregulating immune checkpoint ligands including PD-L1 and PD-L2. We further discuss mechanotransduction signaling cascades that translate physical cues into immunological outcomes, and evaluate emerging therapeutic strategies to normalize matrix stiffness (including ECM-targeting agents, mechanosignaling inhibitors, and mechano-optimized cellular therapies) and their synergistic combination with immune checkpoint blockade. We conclude by highlighting key challenges and future directions for translating mechano-immunological insights into clinical practice.