Pyroptosis‐Activating Nanoplatform Unleashes Metabolic‐Directed Neutrophil Reprogramming to Boost Cancer Immunotherapy

ABSTRACT The clinical efficacy of current immunotherapeutic approaches remained to be constrained by the profoundly immunosuppressive tumor microenvironment (TME). To overcome these obstacles, this study developed a synergistic nanoplatform, HA‐V‐9302@ZIF (HVZ), that synergized pyroptosis induction and metabolic reprogramming. This hyaluronic acid‐cloaked system exploited the enzymatic and acidic TME to synchronously release Zn ^{2 +} from the ZIF‐8 core and the ASCT‐2 inhibitor V‐9302. Pyroptosis induced by Zn ^{2 +} ‐triggered caspase‐1/GSDMD signal released damage‐associated molecular patterns (DAMPs), thereby igniting inflammation and recruiting neutrophils. Simultaneously, metabolic reprogramming by V‐9302 blocked tumor glutamine/leucine uptake, which created a TME leucine niche to drive neutrophil differentiation into antigen‐presenting CD74 ⁺ subsets, and conserved glutamine to revitalize cDC1 function. Crucially, pyroptosis‐driven inflammation provided a triggering factor of innate immunity, meanwhile HVZ mediated metabolic regulation, empowering the antigen presentation of neutrophils and cDC1s, subsequently activating CTLs. Consequently, pyroptosis‐evoked‐CTLs secreted the granzyme B (GzmB), further inducing the pyroptosis by GzmB/GSDME signal, which established a positive feedback cycle against tumor. The synergistic interplay of pyroptosis‐driven immune cell recruitment and immunometabolic reprogramming effectively broke the barriers of antitumor immunity and potentiating immunotherapy responses in vitro and in vivo. This study provided a new perspective for the design of immunotherapy strategies based on pyroptosis and metabolic regulation.