Modulating extracellular matrix stiffness: A strategic approach to boost cancer immunotherapy
Open accessAbstract
The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.
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ECM stiffness triggers mechanotransduction pathways that influence tumor cell behavior, including activation of YAP/TAZ, FAK, and MAPK pathways and modulation of gene expression associated with proliferation, EMT, and drug resistance.
“However, beyond acting as a physical barrier, ECM stiffness also triggers mechanotransduction pathways that profoundly influence tumor cell behavior [91,92]. Mechanical cues generated by a stiffened matrix are sensed through integrin-based focal adhesions and transmitted via cytoskeletal tension to activate intracellular signaling cascades, including Yes-associated protein/Transcriptional coactiv”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [91]
The tumor-cell sections report that ECM stiffness activates integrin-linked FAK signaling and a FAK–Rho–ERK cascade leading to MAPK activation; they also link stiffness to YAP activity, proliferation, and EMT-related changes in gene expression (pages unavailable). The drug-resistance section links stiffness to chemotherapy resistance, but attributes it to increased drug-efflux protein activity and impaired drug delivery, not altered resistance-gene expression. The paper’s text does not establish TAZ activation alongside YAP. (LLM, conf=0.86)
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References 176 · Cited by 398
- Authors
- Mai, Z., Lin, Y., Lin, P., Zhao, X., & Cui, L.
- Affiliations
- Southern Medical University (CN)
- Guangdong Province Stomatological Hospital (CN)
- Corresponding author
- Zhao, Xinyuan
- Cui, Li
- Venue
- Cell Death & Disease
- Published
- 2024-05-01
- Volume
- 15
- Issue
- 5
- Pages
- 307-307
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC11063215
- OpenAlex
- W4396546588
- Cited by
- 398
- References
- 176
- Citations by year
- 2026: 191 · 2025: 165 · 2024: 42
- FWCI
- 21.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82372905, 81901006)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- extracellular matrix stiffness, tumor microenvironment, cancer immunotherapy, extracellular matrix remodeling, cancer-associated fibroblasts, immune checkpoint blockade, adoptive immunotherapy, oncolytic virotherapy, cancer vaccines, biomaterials, tumor immune cells
- MeSH terms
- Animals, Extracellular Matrix, Humans, Immunotherapy, Neoplasms, Tumor Microenvironment
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