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.
NETL
NSTL
Wiley