A “metabolic dual-clamp” strategy for glucose metabolism blockade and cascade-amplified tumor immunotherapy

Immunogenic cell death (ICD) represents a promising approach to convert “cold tumor” into “hot tumor”. However, its induction is often hampered by the immunosuppressive tumor microenvironment fueled by aberrant glucose metabolism. Here, we report a novel “metabolic dual-clamp” strategy inspired by the cooperative pincer movement of crabs to achieve glucose metabolism blockade. Glucose oxidase (GOx) serves as the “external clamp” to deplete extracellular glucose, while 2-deoxy-D-glucose (2-DG) acts as the “internal clamp” to inhibit intracellular glucose metabolism. This synergistic system is co-delivered by a self-assembled DNA nanocage, AS1411-Mn/2-DG-GOx (AMDG). The AMDG not only inhibits glucose metabolism to reverse immunosuppression but also initiates a cascade reaction: Mn 2+ catalyzes H 2 O 2 to O 2 , promoting GOx activity, and generating more H 2 O 2 to enhance Mn 2+ -mediated CDT, ultimately leading to cascaded amplification of ICD. Furthermore, Mn 2+ acts as a STING agonist to activate the cGAS-STING pathway, promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration. Both in vitro and in vivo studies demonstrate that this strategy effectively inhibits tumor glucose metabolism, thereby enhancing ICD-induced antitumor immunity. This study presents the first exploration of the GOx and 2-DG combination, establishing a powerful synergistic treatment paradigm based on glucose metabolism reprogramming.