Mechanical dysfunction: ovarian cancer ascites disables NK cells by suppressing CDC42-driven force generation
6 affiliations
- 1Department of Hepatobiliary Surgery, Key Laboratory for Cancer Prevention and Treatment of Guizhou Province, The Affiliated Hospital of Guizhou Medical University, School of Biology and Engineering (School of Modern Industry for Health and Medicine), Guizhou Medical University
- 2Department of Immunology, School of Basic Medical Sciences, Guizhou Medical University
- 3Obstetrics and Gynecology Department, The Affiliated Hospital of Guizhou Medical University
- 4Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University
- 5Guizhou Medical Sequencing Center, Precision Medicine Research Institute of Guizhou, The Affiliated Hospital of Guizhou Medical University
- 6Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Key Laboratory of Microbio and Infectious Disease Prevention & Control, Guizhou Medical University
Abstract
Introduction: Ovarian cancer ascites creates an immunosuppressive microenvironment that compromises NK cell function, yet the underlying mechanisms remain incompletely understood.
Methods: We used ascites-conditioned NK cells and assessed their mechanophenotypes, including F-actin, cortical tension, and traction force, along with CDC42 activity. Transcriptomic analysis and bidirectional pharmacological manipulation of CDC42 were performed.
Results: Ascites-conditioned NK cells exhibited a paradoxical cytoskeletal state—elevated F-actin yet reduced cortical tension and traction force—indicating a failure to translate actin polymerization into productive mechanical output. Mechanistically, ascites triggered de novo expression of the CDC42 negative regulators, CDC42EP1 and CDC42EP5, leading to suppressed CDC42 activity. Bidirectional pharmacological manipulation of CDC42 reciprocally regulated traction force and cytotoxicity, establishing a causal link between CDC42-dependent mechanics and NK cell killing. The near-perfect correlation between traction force and killing capacity positions traction force as a robust mechanobiomarker of NK cell competence.
Discussion: These findings uncover a previously unrecognized role for CDC42 in governing NK cell mechanics and identify CDC42 as a therapeutically actionable node for restoring anti-tumor immunity in immunosuppressive microenvironments.
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BibTeX
@article{an2026mechanical,
title = {{Mechanical dysfunction: ovarian cancer ascites disables NK cells by suppressing CDC42-driven force generation}},
author = {Chenyi An and Yujun Xu and Ziyu Zhou and Jiong Wang and Xuan Liu and Ting Guo and Zhihua Yan and Lvyang Zhou and Xing Zhao and Rui Qin and Zhu Zeng and Shi Zuo},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1883517},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1883517/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanical dysfunction: ovarian cancer ascites disables NK cells by suppressing CDC42-driven force generation
AU - Chenyi An
AU - Yujun Xu
AU - Ziyu Zhou
AU - Jiong Wang
AU - Xuan Liu
AU - Ting Guo
AU - Zhihua Yan
AU - Lvyang Zhou
AU - Xing Zhao
AU - Rui Qin
AU - Zhu Zeng
AU - Shi Zuo
PY - 2026
DA - 2026/10/16
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1883517
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1883517/full
AB - Introduction: Ovarian cancer ascites creates an immunosuppressive microenvironment that compromises NK cell function, yet the underlying mechanisms remain incompletely understood. Methods: We used ascites-conditioned NK cells and assessed their mechanophenotypes, including F-actin, cortical tension, and traction force, along with CDC42 activity. Transcriptomic analysis and bidirectional pharmacological manipulation of CDC42 were performed. Results: Ascites-conditioned NK cells exhibited a paradoxical cytoskeletal state—elevated F-actin yet reduced cortical tension and traction force—indicating a failure to translate actin polymerization into productive mechanical output. Mechanistically, ascites triggered de novo expression of the CDC42 negative regulators, CDC42EP1 and CDC42EP5, leading to suppressed CDC42 activity. Bidirectional pharmacological manipulation of CDC42 reciprocally regulated traction force and cytotoxicity, establishing a causal link between CDC42-dependent mechanics and NK cell killing. The near-perfect correlation between traction force and killing capacity positions traction force as a robust mechanobiomarker of NK cell competence. Discussion: These findings uncover a previously unrecognized role for CDC42 in governing NK cell mechanics and identify CDC42 as a therapeutically actionable node for restoring anti-tumor immunity in immunosuppressive microenvironments.
SN - 1664-3224
ER -