Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer, associated with poor prognosis. Understanding the mechanisms by which TNBC cells evade the anticancer activity of natural killer (NK) cells is crucial for developing effective therapeutic strategies. ELK3, a transcription factor overexpressed in TNBC, is known to regulate epithelial-mesenchymal transition and immune responses. In this study, we identified and validated downstream targets of ELK3 implicated in the immune sensitivity of TNBC cells to NK cells. Gene expression profiling and molecular analysis revealed that ELK3 directly suppresses the expression of CYFIP2, a key inhibitor of actin filament accumulation. Functional studies demonstrated that the ELK3-CYFIP2 axis in TNBC modulates actin dynamics and impacts NK cell-mediated cytotoxicity. Specifically, ELK3 knockdown (ELK3KD) resulted in reduced actin accumulation at NK cell contact sites, significantly enhancing NK cell cytotoxicity compared to wild-type (WT) cells. Conversely, silencing CYFIP2 in ELK3KD cells restored actin accumulation and reduced NK cell-mediated killing.

Further molecular and pharmacological investigations revealed that the ELK3-CYFIP2 axis plays a dual role in TNBC cells by: (1) regulating filopodia-mediated migration and adhesion through actin accumulation, and (2) modulating sensitivity to NK cells by controlling actin remodeling at contact sites. Kaplan-Meier survival analyses suggested a strong correlation between the ELK3-CYFIP2 axis and TNBC patient outcomes, with ELK3-mediated repression of CYFIP2 associated with poor prognosis.

In conclusion, the ELK3-CYFIP2 axis emerges as a critical regulator of actin cytoskeletal dynamics, orchestrating both the metastatic potential and immune evasion in TNBC. Targeting this pathway may offer a novel therapeutic approach to enhance NK cell-mediated immunotherapy in TNBC.