Mechanical dysfunction: ovarian cancer ascites disables NK cells by suppressing CDC42-driven force generation

Ovarian cancer ascites creates an immunosuppressive microenvironment that compromises NK cell function, yet the underlying mechanisms remain incompletely understood.

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.

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.

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.