Interstitial flow promotes macrophage polarization toward an M2 phenotype

Area of Science:

• Immunology
• Biophysics
• Oncology

Background:

• Tumor tissues exhibit increased interstitial fluid flow (IF) from the tumor to surrounding stroma.
• Macrophages are key regulators of tumor progression within the tumor microenvironment.
• The impact of mechanical stimuli, like IF, on macrophage phenotypes remains largely unexplored.

Purpose of the Study:

• To investigate the effects of interstitial fluid flow (IF) on macrophage phenotypes.
• To elucidate the underlying mechanotransduction pathways involved in IF-mediated macrophage polarization.

Main Methods:

• Utilized three-dimensional biomimetic models to simulate tumor interstitial fluid flow.
• Quantified macrophage responses to pathophysiological levels of IF (∼3 µm/s).
• Investigated integrin/Src-mediated mechanotransduction pathways involving STAT3/6.

Main Results:

• Macrophages sense and respond to tumor-relevant IF levels.
• IF induces M2-like macrophage polarization via integrin/Src/STAT3/6 pathways.
• IF enhances macrophage migration speed and their ability to promote cancer cell migration.
• IF directs macrophages to migrate against the flow direction.

Conclusions:

• Interstitial fluid flow (IF) is a significant mechanical stimulus that polarizes macrophages towards an M2-like phenotype.
• IF not only polarizes macrophages but also recruits them towards tumor masses, potentially driving cancer cell invasion.
• IF emerges as a critical regulator of the tumor immune microenvironment and cancer progression.