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

Authors

Juan Zhang, Yulong Han, Huan Gao, Mi Zhang, Xiaoqian Gao, Yan Zhou, Lin Wang, Lin Nan, Binghe Xu, Ting Wen, Jin Yang, Feng Xu

Published in

Cell reports. Volume 45. Issue 10. Pages 118045. Sep 24, 2026. Epub Sep 24, 2026.

Abstract

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.

PMID:
42789388
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.

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