RelB drives integrin-mediated stress tolerance and relapse in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) often relapses after chemotherapy due to chemoresistant cancer stem-like cells (CSCs). NF-κB signaling, previously shown to enhance stemness traits, was investigated for its role in post-treatment tumor regrowth. Here, we found that NF-κB subunits RelA and RelB jointly regulate extracellular matrix genes but differentially control integrin subunits: RelA regulates ITGAV (αV) and RelB regulates ITGB3 (β3). Integrin αVβ3 expression is upregulated on CSCs, and this is partially driven by NF-κB activation. In vivo models demonstrate that αVβ3+ cells have higher tumor-initiating capacity and comprise over 90% of cells from relapsed tumors. Cells expressing RelB and αVβ3 preferentially grow on mesentery at relapse. Targeting this pathway, combined RelB knockdown and inhibition of αVβ3 eliminated stress-tolerant CSCs, reduced tumor burden, and extended survival. These findings highlight integrins as promising therapeutic targets and reveal distinct roles for NF-κB subunits in regulating metastasis and relapse in HGSOC.