High tumor extracellular matrix stiffness in solid tumors drives immune suppression and therapy resistance via YAP1

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Frontiers in Medicine Published May 30, 2026 Medically reviewed May 30, 2026 Study authors: Fei Wu, Po Zhang, Weichi Wu, Tian Hou, Xiaobing Jiang, Tao Huang DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Note that high tumor stiffness attenuates immunity and upregulates YAP1 in solid tumors.

This narrative review explores the impact of tumor extracellular matrix stiffness within the context of solid tumors. The scope covers various cellular and molecular alterations driven by this physical property. The authors synthesize findings indicating that stiffness attenuates T-cell and NK cell functions. Additionally, macrophage and dendritic cell polarization shifts towards immunosuppressive phenotypes. Cancer-associated fibroblasts remain persistently activated under these conditions. These environmental changes also induce tumor cell epithelial-mesenchymal transition and upregulate immune checkpoints. High expression of YAP1 is associated with immunotherapy resistance. The review does not report specific sample sizes or numerical effect sizes for these outcomes. Safety data and adverse events were not reported. The authors note that strategies such as enzymatic degradation, targeting mechanotransduction pathways, employing anti-fibrotic drugs, and developing intelligent combination therapies have emerged. These approaches represent potential avenues for overcoming the barriers posed by a stiff tumor microenvironment. The review highlights the complexity of the tumor microenvironment in solid tumors.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Tumor matrix stiffness, a pivotal physical attribute of the tumor microenvironment, has evolved from a passive physical barrier to an active immunoregulatory platform, profoundly impacting the initiation and effector phases of anti-tumor immune responses. This review systematically elaborates on the dual mechanisms that drive immunosuppression. Directly, stiffness attenuates T-cell and natural killer (NK) cell functions by activating pathways such as Yes-associated protein (YAP)/Transcriptional co-activator with PDZ-binding motif (TAZ) and Piezo-type mechanosensitive ion channel component 1 (Piezo1). It also drives the polarization of macrophages and dendritic cells towards immunosuppressive phenotypes. Indirectly, stiffness fosters an immune escape ecosystem by persistently activating cancer-associated fibroblasts, inducing tumor cell epithelial-mesenchymal transition, and upregulating immune checkpoints. Consequently, strategies such as enzymatic degradation, targeting mechanotransduction pathways, employing anti-fibrotic drugs, and developing intelligent combination therapies have emerged, aiming to soften tumors and reverse immunosuppression. Clinical studies confirm that high expression of the mechanosignaling hub Yes-associated protein 1 (YAP1) is associated with resistance to immunotherapy. In the future, integrating mechanobiology, immunometabolism, and smart materials to develop precise multimodal combination strategies holds promise for reversing the “cold tumor” microenvironment and opening new avenues to overcome immunotherapy resistance in solid tumors.