Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy - review article

Sep 21, 2026

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Extracellular matrix (ECM) stiffness is presented as a key biomechanical driver of cancer progression, shaping malignant cancer-cell behaviors through ECM remodeling. The review synthesizes mechanisms regulating ECM remodeling, emphasizing cancer-associated fibroblast activation and ECM protein accumulation and crosslinking, and explains how stiffness influences both tumor and immune-cell functions. It further analyzes how ECM stiffness impacts responses to immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, while outlining translational challenges and the need for biomaterials and strategies that better mimic native ECM.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

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Introduction

[www.nature.com/cddis](www.nature.com/cddis) REVIEW ARTICLE OPEN Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy Zizhao Mai1, Yunfan Lin1, Pei Lin1, Xinyuan Zhao 1 ✉ and Li Cui 1 ✉ © The Author(s) 2024 | | | | | --- | --- | --- | | | 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. | | | | | Cell Death and Disease (2024)15:307; [https://doi.org/10.1038/s41419-024-06697-4](https://doi.org/10.1038/s41419-024-06697-4) | | | | | | FACTS 1. Extracellular matrix (ECM) stiffness plays a critical role in promoting cancer initiation and progression by regulating the malignant behaviors of cancer cells. 2. Key factors regulating ECM remodeling include the activation of cancer-associated ﬁbroblasts and the accumulation and crosslinking of ECM proteins. 3. ECM stiffness forms a formidable physical barrier around tumors, hindering immune cell inﬁltration and impeding the precise delivery of immunotherapeutic agents. OPEN QUESTIONS 1. What is the role of ECM stiffness in altering the tumor microenvironment, and how does it subsequently affect tumor progression and therapeutic outcomes? 2. What are the effects and underlying mechanisms of ECM stiffness on immune cell behaviors within the tumor microenvironment? 3. How can targeting ECM stiffness be optimized to achieve maximal efﬁcacy in various types of cancer immunotherapy? INTRODUCTION The process of tumorigenesis depends on two primary factors: genetic and epigenetic alterations within tumor cells, and the dynamic interactions within the tumor microenvironment (TME). The immunosuppressive properties of the TME are crucial in dampening the host’s immune response. The TME includes blood vessels, immune cells, stromal cells, and the extracellular matrix (ECM). Notably, the ECM consists of proteins, mainly divided into ﬁbrous proteins and glycosaminoglycans (GAGs), providing both structural and biochemical support to the resident cells [1, 2]. ECM stiffness, a critical biomechanical property, denotes the resistance of the ECM to deformation when subjected to mechanical stress. It is quantitatively assessed in terms of the elastic modulus. In a physiological context, the rigidity of the ECM is ﬁnely balanced, integral to maintaining cellular homeostasis and tissue architecture. However, aberrant alterations in ECM stiffness are implicated in many pathological conditions, particularly in cancer. The ECM dynamically adapts to the progression of cancer, exhibiting shifts in its composition, topological structure, directionality, and notably, its mechanical properties, which directly inﬂuence ECM stiffness [3]. These alterations in ECM stiffness subsequently drive changes in cellular mechanobiology, which includes modiﬁcations in cytoskeletal tension and the activation o

FAQs

How does ECM stiffness contribute to cancer initiation and progression?

ECM stiffness regulates malignant behaviors of cancer cells and promotes cancer initiation and progression within the tumor microenvironment.

What mechanisms regulate ECM remodeling and ECM stiffness?

Key mechanisms include activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins.

How does ECM stiffness affect immunotherapy outcomes?

ECM stiffness can form a physical barrier that limits immune infiltration and drug delivery, and it can also enhance immune evasion by altering immune checkpoint molecule expression, contributing to reduced effectiveness of immunotherapies.

Sep 21, 2026

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