Increased extracellular fluid viscosity drives M2-like macrophage polarization to promote breast cancer progression and immunotherapy resistance

Breast cancer progression and therapy resistance remain major clinical obstacles. Although extensive research has focused on biochemical signals within the tumor microenvironment (TME), the contribution of physical cues, particularly the viscosity of interstitial extracellular fluid (ECF), has been largely overlooked. Here, we provide mechanobiological evidence that elevated ECF viscosity in the TME drives immunosuppressive M2-like macrophage polarization, which in turn promotes breast cancer growth and metastasis. Notably, increased ECF viscosity contributes to resistance to anti-PD-1 immunotherapy. We demonstrate that high ECF viscosity skews macrophages toward a pro-tumoral phenotype through integrin-mediated mechanotransduction, which activates focal adhesion kinase (FAK) and downstream signal transducer and activator of transcription 3 (STAT3), along with extensive cytoskeletal remodeling and nuclear deformation. Collectively, these findings establish ECF viscosity as a critical physical and immunological regulator and suggest it as a potential biophysical therapeutic target in breast cancer.