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

Abstract

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.