Research progress on tumor extracellular matrix stiffness and immunosuppression

Area of Science:

• Oncology
• Immunology
• Biophysics

Background:

• Tumor matrix stiffness is a key physical factor in the tumor microenvironment.
• It has shifted from a passive barrier to an active regulator of anti-tumor immune responses.

Purpose of the Study:

• To systematically review the dual mechanisms by which tumor stiffness drives immunosuppression.
• To explore emerging therapeutic strategies targeting tumor matrix stiffness.

Main Methods:

• Literature review of studies on tumor matrix stiffness and its impact on the immune system.
• Analysis of direct and indirect mechanisms of immunosuppression mediated by stiffness.
• Examination of therapeutic strategies and clinical findings.

Main Results:

• Stiffness directly impairs T-cell and NK cell functions via YAP/TAZ and Piezo1 pathways.
• Stiffness promotes immunosuppressive phenotypes in macrophages and dendritic cells.
• Stiffness indirectly promotes immune escape by activating cancer-associated fibroblasts and epithelial-mesenchymal transition, upregulating immune checkpoints.
• High YAP1 expression correlates with immunotherapy resistance.

Conclusions:

• Tumor matrix stiffness is a significant driver of immunosuppression and immunotherapy resistance.
• Strategies to soften tumors and target mechanotransduction pathways are crucial.
• Integrating mechanobiology, immunometabolism, and smart materials may overcome the "cold tumor" microenvironment and resistance to immunotherapy.