ABSTRACT Glioblastoma (GBM) exhibits profound tumor metabolic plasticity and an immunosuppressive, macrophage‐rich microenvironment, leading to poor and short‐lived therapeutic responses. Here, we report nanoMetaboGate, a pH‐responsive nanoplatform that couples metabolic restriction with immune remodeling. A macrophage‐GBM hybrid membrane coating enables immune evasion, homotypic targeting, and blood‐brain barrier penetration. In acidic GBM tissue, the ZIF nanocore disassembles to release Zn 2+ and the creatine‐uptake inhibitor guanidinopropionic acid (GPA), establishing a dual checkpoint blockade of the creatine metabolic axis. Zn 2+ attenuates macrophage glycolysis to alleviate immunosuppression and reduce creatine supply, while GPA inhibits creatine uptake in GBM cells, diminishing stem‐like traits. Meanwhile, Zn 2+ triggers cGAS‐STING activation, together with creatine limitation, synergistically enhances oxidative injury. Collectively, these coordinated actions disrupt metabolic buffering, remodel the suppressive niche, and promote tumor cell death. This work pioneers a GBM‐tailored strategy leveraging ion‐assisted metabolic intervention for improved therapeutic control.
Zhang et al. (Thu,) studied this question.