Work

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

Year: 2025

Type: article

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 − , CO 3 2− , PO 4 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@FeF 2 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. • Demonstrating F − -mediated downregulation of β-catenin expression with concurrent upregulation of its endogenous inhibitor DKK1 in malignant cells. • Engineering novel 5-Fu@FeF 2 nanomedicine (FFN-5) to effectively reduce cancer stemness while enhancing 5-Fu cytotoxicity to induce pyroptosis in tumor cells. • Reversing the immunosuppressive TME to significantly enhance chemoimmunotherapy response.

Source: Bioactive Materials

DOI: 10.1016/j.bioactmat.2025.10.011