Metal fluoride nanoregulators reverse therapeutic resistance via stemness remodeling to trigger pyroptosis for...

Chemoresistance and immunosuppression serve as major obstacles that compromise the therapeutic efficacy of chemoimmunotherapy. Herein, we reported a novel chemoimmunotherapy strategy employing metal fluoride to modulate Wnt/β-catenin signaling, effectively remodeling treatment resistance and eliciting pyroptosis-mediated immune activation. Through systematic screening of various nonmetallic anions (F^-, Cl^-, Br^-, I^-, CO₃ ^2-, PO₄ ^3-, S^2-, and Se^2-), we identified F^- as an effective inhibitor of β-catenin expression and tumor stemness. The synergistic combination of F^- with chemotherapy significantly attenuated tumor stemness and enhanced treatment efficacy. We further engineered 5-Fu@FeF₂ nanomedicine (FFN-5) and investigated its chemoimmunotherapeutic effects. FFN-5 potently suppressed β-catenin expression, effectively diminishing cancer stemness while augmenting the cytotoxicity of 5-Fu, ultimately triggering pyroptosis. Local administration of FFN-5 not only inhibited tumor growth but also remodeled the immunosuppressive tumor microenvironment (TME), thereby promoting antitumor immunity. When combined with immune checkpoint blockade (ICB), this combined approach triggered a potent systemic immune response, effectively controlling both primary and distant lesions. Furthermore, the unique stemness-modulating properties of F-based nanomodulators significantly suppressed tumor metastasis. In summary, we demonstrated that F^- effectively suppressed tumor stemness, and developed an innovative FFN-5 nanoplatform that enhanced chemoimmunotherapy by modulating stemness-dependent cell death mechanisms, suggesting a promising strategy to overcome resistance to cancer treatment.