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

Mai, Zizhao; Lin, Yunfan; Lin, Pei; Zhao, Xinyuan; Cui, Li

doi:10.1038/s41419-024-06697-4

Cited by 38 publications

(4 citation statements)

References 173 publications

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“…These results highlight several potential therapeutic strategies. Modifying ECM stiffness to disrupt the supportive environment for M2 macrophages could inhibit tumor progression [68].…”

Section: Discussionmentioning

confidence: 99%

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Sapudom,

Tipay,

Teo

2024

Preprint

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The tumor microenvironment (TME), which is composed of various cell types and the extracellular matrix (ECM), plays crucial roles in cancer progression and treatment outcomes. However, the impact of the mechanical properties of the ECM, specifically collagen fibril alignment and crosslinking, on macrophage behavior and polarization is less understood. To investigate this, we reconstituted 3D collagen matrices to mimic the physical characteristics of the TME. Our results demonstrated that stiffening the matrix through the alignment or crosslinking of collagen fibrils promotes macrophage polarization toward the anti-inflammatory M2 phenotype. This phenotype is characterized by increased expression of CD105 and CD206 and a distinct cytokine secretion profile. The increased stiffness and aligned fibrils activate mechanotransduction pathways, notably integrin β1 and PI3K signaling, leading to increased IL-4 secretion, which acts in an autocrine manner to further promote M2 polarization. Interestingly, these stiffened microenvironments also suppressed the proinflammatory response. In coculture experiments with breast cancer cell lines (MDA-MB-231 and MCF-7), macrophages within stiffened or aligned matrices significantly increased cancer cell proliferation and invasion. These findings suggest that the mechanical properties of the ECM, specifically its alignment and crosslinking, create a more favorable environment for tumor progression by modulating macrophage activity. Overall, our study underscores the critical role of ECM mechanics in shaping immune cell behavior within the TME, highlighting the potential for therapies that target ECM properties and macrophage polarization to inhibit cancer progression and enhance treatment efficacy.

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“…These results highlight several potential therapeutic strategies. Modifying ECM stiffness to disrupt the supportive environment for M2 macrophages could inhibit tumor progression [68].…”

Section: Discussionmentioning

confidence: 99%

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Sapudom,

Tipay,

Teo

2024

Preprint

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“…ECM stiffness and architecture) may greatly affect the intracellular mechanical state of cells (e.g. changing mechanical properties of cells and/or influencing the stress distribution within the cell) [ 19 , 196 , 197 ]. These changes in cell state may ultimately translate into the regulation of nanoparticle uptake.…”

Section: Mechanical Cues Alter the Endocytosis Pathways Of Nanoparticlesmentioning

confidence: 99%

Impact of mechanical cues on key cell functions and cell-nanoparticle interactions

Elblová,

Lunova,

Dejneka

et al. 2024

Discover Nano

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In recent years, it has been recognized that mechanical forces play an important regulative role in living organisms and possess a direct impact on crucial cell functions, ranging from cell growth to maintenance of tissue homeostasis. Advancements in mechanobiology have revealed the profound impact of mechanical signals on diverse cellular responses that are cell type specific. Notably, numerous studies have elucidated the pivotal role of different mechanical cues as regulatory factors influencing various cellular processes, including cell spreading, locomotion, differentiation, and proliferation. Given these insights, it is unsurprising that the responses of cells regulated by physical forces are intricately linked to the modulation of nanoparticle uptake kinetics and processing. This complex interplay underscores the significance of understanding the mechanical microenvironment in shaping cellular behaviors and, consequently, influencing how cells interact with and process nanoparticles. Nevertheless, our knowledge on how localized physical forces affect the internalization and processing of nanoparticles by cells remains rather limited. A significant gap exists in the literature concerning a systematic analysis of how mechanical cues might bias the interactions between nanoparticles and cells. Hence, our aim in this review is to provide a comprehensive and critical analysis of the existing knowledge regarding the influence of mechanical cues on the complicated dynamics of cell-nanoparticle interactions. By addressing this gap, we would like to contribute to a detailed understanding of the role that mechanical forces play in shaping the complex interplay between cells and nanoparticles.

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“…Conversely, high matrix stiffness in the TME of breast carcinoma can also support cancer metastasis by inducing EMT and activating mechanotransduction pathways such as TWIST1-G3BP2 and EPHA2/LYN/TWIST1 ( 43 , 44 ). Thus, ECM stiffness promotes a variety of tumor-supporting activities including cytoskeleton changes, increased metabolic pathways as well as cancer cell proliferation, invasiveness and aggressiveness ( 45 ).…”

Section: Impact Of Ecm Remodeling On Cancer Progressionmentioning

confidence: 99%

“…Furthermore, activities of different immune cells within the tumor microenvironment are affected by ECM stiffness. For example, antigen presentation as well as T-cell migration and infiltration to the tumor are reduced with stiff and remodeled ECM, while increased proliferation of T cells and antitumor immunity are associated with a less-stiff ECM ( 45 ).…”

Section: Impact Of Ecm Remodeling On Cancer Progressionmentioning

confidence: 99%

The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics

Prakash,

Shaked

2024

Cancer Discovery

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The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression. This review discusses critical issues in this field including how the ECM influences treatment outcome, how cancer therapies affect ECM remodeling, and the challenges associated with targeting the ECM. Significance: The intricate relationship between the extracellular matrix (ECM) and cancer therapeutics reveals novel insights into tumor biology and its effective treatment. While the ECM may protect tumors from anti-cancer agents, recent research highlights the paradoxical role of therapy-induced ECM remodeling in promoting treatment resistance and tumor progression. This review explores the key aspects of the interplay between ECM and cancer therapeutics.

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

Cited by 38 publications

References 173 publications

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Impact of mechanical cues on key cell functions and cell-nanoparticle interactions

The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics

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