Nanoceria-curcumin nanoplatform enhances radiotherapy efficacy in triple-negative breast cancer via microenvironmental redox modulation and TNF-α-NF-κB/inflammatory program suppression.

Triple-negative breast cancer (TNBC) derives only limited clinical benefit from radiotherapy (RT), partly due to abnormalities in the tumor microenvironment and dysregulated signaling pathways. By integrating TNBC cases from the METABRIC and TCGA cohorts, we implemented an analysis framework centered on RT-by-gene interaction terms, implicating TNF-α-NF-κB signaling and inflammatory response as potential effect modifiers of RT benefit. Based on a pathway-guided polyphenol-gene interaction screen, curcumin (Cur) was prioritized as a modulator of TNF-α-NF-κB/inflammation-related programs. We then engineered a multifunctional nanoplatform (TCC) that couples catalytic modulation of the tumor microenvironment with suppression of adaptive pro-survival programs. TCC was built on pH-responsive nanoceria (CeO2 nanozymes) to modulate redox homeostasis and alleviate hypoxia, loaded with Cur, and coated with D-α-tocopherol polyethylene glycol succinate (TPGS) to improve stability and cellular uptake; cRGD was further introduced to generate cRGD-TCC for enhanced tumor targeting. In vitro and in vivo, TCC promoted G2/M-phase arrest, amplified RT-induced reactive oxygen species generation and DNA damage, and attenuated TNF-α-NF-κB/inflammatory programs and markers of inflammation, survival, and invasion. Collectively, TCC provides an integrated radiosensitization strategy that addresses microenvironmental barriers and adaptive tumor signaling, thereby potentially enhancing RT response in TNBC.