Work

Multifunctional cascade nanosystem consumes glucose to trigger enhanced pyroptosis and cuproptosis for tumor immunotherapy

Year: 2026

Type: article

Abstract: Immunogenic cell death (ICD) bridged local therapy and systemic immune activation by releasing damage-associated molecular patterns (DAMPs) that provoked antitumor responses. Pyroptosis, a pro-inflammatory cell death mode, induced local tumor demise and releases cytokines that facilitated immune activation. In this study, we constructed a multifunctional cascade nanosystem CaO 2 /Cu-ZIF8/GOX (CaO 2 /CZ/GOX) that triggered mitochondrial oxidative stress through glucose consumption and ion homeostasis disturbance and cuproptosis, thereby amplifying tumor pyroptosis. The nanosystem utilized acid-responsive Cu-ZIF8 (CZ) as a carrier to load CaO 2 and glucose oxidase (GOX). In the acidic tumor microenvironment (TME), CaO 2 initiated cascaded H 2 O 2 generation, while GOX concurrently consumed glucose and catalytically generated H 2 O 2 , synergistically exacerbating ion homeostasis disruption and mitochondrial oxidative stress. Meanwhile, Cu 2+ released from Cu-ZIF8 participated in Fenton-like reactions to generate hydroxyl radicals (·OH), and accumulated Cu 2+ further triggered FDX1-mediated cuproptosis. Collectively, these events resulted in reactive oxygen species (ROS) accumulation, ion homeostasis disruption, and mitochondrial damage, ultimately activating tumor cell pyroptosis and cuproptosis. In vitro and in vivo assays confirmed that CaO 2 /CZ/GOX NPs efficiently consumed glucose, selectively accumulated in tumor, and exhibited favorable biocompatibility. Moreover, they significantly inhibited Hepa1-6 tumor cell proliferation, effectively suppressed tumor recurrence and activated antitumor immunity. Overall, this nanosystem integrated a cascade of metabolic intervention, oxidative damage, cuproptosis, pyroptosis, and immune activation, offering a new strategy for tumor metabolic regulation and immune microenvironment remodeling.

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2026.103772