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

Abstract

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 C₇₀ fullerene with hyaluronic acid (HA)-modified zeolitic imidazolate framework-8 (ZIF-8) to enhance tumor immunogenicity and reprogram the TME. The resulting HA-C₇₀@ZIF-8 nanocomposites exploit HA-mediated CD44 targeting to promote selective tumor uptake and retention. Once internalized, acidic lysosomal conditions trigger Zn²⁺ 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 C₇₀ 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.