Nitrofurantoin Enhances Cuproptosis Sensitivity in Cancer Cells Through SLC11A2-Dependent Copper Homeostasis

Knockdown of SLC11A2 significantly reduced intracellular copper signaling and reversed the sensitizing effect of NFT on cuproptosis. Furthermore, transcriptomic analysis identified PPP1R15A as a key node of the integrated stress response, which amplifies cuproptosis-related proteotoxicity through endoplasmic reticulum stress. In three-dimensional tumor spheroid and in vivo models, NFT enhanced the antitumor efficacy of cuproptosis inducers, whereas SLC11A2 knockdown suppressed this effect.

Analyses of public tumor cohorts and immunotherapy cohorts revealed that SLC11A2 and PPP1R15A expression correlated with survival outcomes and immunotherapy responses in certain tumor types. Collectively, these findings provide a mechanistic framework for understanding how concomitant medication influences tumor cell death sensitivity and suggest SLC11A2 as a potential target for predicting and enhancing cuproptosis-directed therapeutic responses.