Inducing pyroptosis and reprogramming macrophage via zeolitic imidazolate framework encapsulated-fullerene for two-pronged tumor immunotherapy

Immunogenic antigen downregulation combined with an immunosuppressive tumor microenvironment (TME) remain major barriers to effective treatment of “cold” tumors. Here, we report a dual-functional nanotherapy that integrates C 70 fullerene with hyaluronic acid (HA)–modified zeolitic imidazolate framework-8 (ZIF-8) to enhance tumor immunogenicity and reprogram the TME. The resulting HA-C 70 @ZIF-8 nanocomposites exploit HA-mediated CD44 targeting to promote selective tumor uptake and retention. Once internalized, acidic lysosomal conditions trigger Zn 2+ release from ZIF-8, causing ion overload, caspase-1 activation, gasdermin D cleavage, and pyroptotic tumor cell death accompanied by the release of damage-associated molecular patterns (DAMPs). Concurrently, encapsulated C 70 facilitates metabolic reprogramming of tumor-associated macrophages (TAMs) from an M2-to M1-like phenotype, thereby alleviating immunosuppression. Together, these mechanisms elicit robust immune activation and potentiate the efficacy of immune checkpoint blockade, offering a streamlined and impactful strategy for personalized tumor therapy and paving the way for novel approaches to highly effective immunotherapy. Immunogenic antigen downregulation and an immunosuppressive tumor microenvironment hinder “cold” tumor treatment. This study introduces HA-C 70 @ZIF-8 nanocomposites, combining C 70 fullerene and HA-modified ZIF-8 for CD44-targeted delivery. They induce pyroptosis via Zn 2+ -triggered caspase-1 activation and TAM repolarization, enhancing tumor immunogenicity and boosting immune checkpoint inhibitor efficacy. • CD44-targeted HA-C 70 @ZIF-8 enhances tumor cell uptake and retention. • Zn 2+ release triggers caspase-1/GSDMD-mediated pyroptotic cell death. • Pyroptosis-driven DAMP release initiates immunogenic cell death. • C 70 fullerene repolarizes TAMs toward proinflammatory M1 phenotype. • Synergizes with checkpoint inhibitors to treat immunologically cold tumors.