Comments on ‘Vimentin intermediate filaments coordinate actin stress fibers and podosomes to determine the extracellular matrix degradation by macrophages’

The cytoskeleton, primarily composed of actin filaments, microtubules, and intermediate filaments, provides structural support and is involved in various cellular processes such as cell adhesion, motility, and phagocytosis (Pollard and Cooper, 2009; Etienne-Manneville, 2013, 2018). Cytoskeletal interactions have attracted extensive research attention in the recent years. Actin filaments drive membrane protrusion and contractile forces during chemotaxis and phagosome formation, while microtubules facilitate organelle transport, polarization, and sustained directional movement by stabilizing leading-edge dynamics (Etienne-Manneville, 2013). Intermediate filaments, particularly vimentin intermediate filaments, contribute to mechanical resilience and modulate inflammatory responses by interacting with adhesion complexes and signaling molecules (Herrmann et al., 2007; Huynh et al., 2024; Pradeau-Phelut and Etienne-Manneville, 2024). Emerging evidence highlights that crosstalk between cytoskeletal networks fine-tunes macrophage adaptation to microenvironmental cues, such as substrate stiffness or pathogen contact (Ory et al., 2002; Benes et al., 2006). For example, when the interaction between actin filaments and microtubules is disrupted, the efficiency of macrophage chemotaxis may be reduced and the formation of phagosomes may be impaired, thus affecting the ability of macrophages to clear pathogens. Such disruption of cytoskeletal interplay can severely impair the effector functions of macrophages, which further emphasizes their central role in innate immunity and the maintenance of tissue homeostasis (Mylvaganam et al., 2021).

In a recent article published in Developmental Cell, Huang et al. (2025) explored how vimentin intermediate filaments, actin stress fibers, and podosomes interact to influence macrophage-mediated extracellular matrix (ECM) degradation, with implications for tumor progression and potential therapeutic strategies. Macrophages play crucial roles in innate immune defense, tissue repair, and tumor progression. They possess the ability to degrade the ECM, which is essential for various physiological and pathological processes, including tissue morphogenesis and tumor metastasis. However, the specific roles of different cytoskeletal structures, particularly intermediate filaments, in controlling ECM degradation by macrophages are not fully understood (Hu et al., 2022). This study employed a comprehensive approach that combined advanced imaging techniques, genetic knockouts, and biochemical assays to elucidate the mechanisms underlying cytoskeleton–macrophage interactions. Immunofluorescence imaging revealed that macrophages exhibit heterogeneity in their ECM degradation capabilities, which correlates with distinct actin organization. Macrophages with tightly organized actin structures (Actin^Tight) implemented more efficient ECM degradation than those with loose actin structures (Actin^Loose). To further investigate the role of stress fibers, the authors utilized live-cell imaging techniques and discovered that stress fibers are involved in intracellular transport and lysosomal degradation of ECM proteins in macrophages. The experimental results demonstrated that disrupting the formation of stress fibers significantly impairs the efficiency of ECM degradation by macrophages.

Vimentin, an intermediate filament protein, plays a crucial role in the structure and function of various cell types (Lowery et al., 2015) and has been shown to control acto-myosin through Rho (van Bodegraven and Etienne-Manneville, 2020). To better understand the function of vimentin in macrophages, Huang et al. (2025) deleted vimentin in THP-1 monocyte-derived macrophages and quantified actin organization. These experiments revealed that vimentin is essential for maintaining the structural integrity and organization of podosomes and stress fibers. Vimentin knockout disrupts the balance between stress fibers and podosomes, leading to impaired ECM degradation. To explore potential mechanism for vimentin to regulate the actin turnover, the authors performed RNA sequencing and identified integrin CD11b (ITGAM, MAC-1) as a downstream regulator of vimentin. Vimentin depletion leads to the downregulation of CD11b, which in turn affects podosome turnover and the distribution of matrix metalloproteinase (MMP) on the cell membrane, impairing ECM degradation. These experiments demonstrated that vimentin regulates ECM degradation by macrophages through CD11b. However, the mechanism by which vimentin controls CD11b transcriptional regulation remains to be elucidated and could involve both signaling and mechanical properties.

To further understand the role of vimentin in the function of tumor-associated macrophages, Huang et al. (2025) checked the expression and distribution of vimentin in lung adenocarcinoma tissue sections and THP-1 macrophages. These experiments demonstrated that M2-type macrophages have a tightly organized vimentin network and podosome distribution. Transwell assay and 3D spheroid migration assay conducted in vitro revealed that vimentin-mediated cytoskeletal organization in M2-type macrophages contributes to tumor invasion. In vivo subcutaneous tumor formation experiments further validated that vimentin enhances the ability of M2-type macrophages to degrade ECM.

Collectively, the findings from Huang et al. (2025) advance our understanding of the complex interplay between the cytoskeleton and macrophage function, particularly in the context of ECM degradation (Figure 1), which illustrates the link between the expression of vimentin and ECM remodeling together with other recent reports (van Bodegraven et al., 2023; Ho Thanh et al., 2024). Moreover, these findings provide new insights into the mechanisms underlying macrophage-mediated ECM degradation and also highlight potential therapeutic targets for modulating macrophage functions in diseases. Future research should focus on elucidating the molecular mechanisms governing cytoskeletal function in macrophages and exploring the clinical applications of these findings.

Figure 1.

The vimentin intermediate filament network plays a critical role in modulating the spatial organization of podosomes and stress fibers. This regulatory function directly influences the capacity for ECM degradation by facilitating the membrane localization of MT1-MMP, thereby determining whether the ECM degradation is potent or slight. WT, wild-type; VIM KO, vimentin knockout.