Disruption of NF‐κB‐Mediated Copper Homeostasis Sensitizes Breast Cancer to Cuproptosis

Copper plays a key role in inflammation and recent tumorigenesis. However, copper homeostasis and its role in cuproplasia and cuproptosis for cancer intervention remain incompletely explored. Here, it is unveiled that copper enhances the NF-κB pathway by directly binding to transforming growth factor β-activated kinase 1 (TAK1), thereby promoting TRAF2 interaction with and mediation of TAK1 ubiquitination and activation, leading to IκB kinase β (IKKβ) activation and mediating copper's inflammatory and oncogenic functions. Notably, copper is indispensable for TNFα/LPS-induced NF-κB activation and subsequent PD-L1 promotion. Thus, copper chelators offer protection against acute infection in murine models. Meanwhile, NF-κB represses copper uptake by negatively controlling the expression of copper transporter 1 (CTR1) transcriptionally, providing a negative feedback regulation for maintaining copper homeostasis. As a result, targeting NF-κB appears to elevate CTR1 expression, leading to excessive copper uptake and downstream MAPK and AKT activation, in turn, conferring resistance to anti-NF-κB therapies. Therefore, disruption of NF-κB not only synergizes with copper chelators to overcome drug resistance and cuproplasia, but also combines with copper ionophores to facilitate cuproptosis, providing a dual approach for combating chronic inflammation-driven cancers.