A High‐Loading Zn Single‐Atom Nanozyme Targets the Zn/HIF‐1α/GLUT1 Axis to Disrupt Glucose Metabolic Reprogramming and Remodel the Tumor Immune Microenvironment

ABSTRACT Highly metastatic osteosarcoma exhibits marked resistance to conventional therapies, driven by glucose‐metabolic reprogramming together with disturbed zinc homeostasis. This study reveals that the TRPML1/HIF‐1α/GLUT1 axis as a mechanistic link between lysosomal zinc homeostasis and glucose‐metabolic regulation, thereby dictating tumor cell fate. On this basis, we developed a TRPML1‐activation‐based single‐atom nanozyme platform with dual enzymatic activities (ZMG@CS) to synchronously collapse ionic and redox homeostasis within lysosomes. Following the lysosomal accumulation of ZMG@CS, high‐density Zn single‐atom sites enabled peroxidase‐like catalysis, whereas the delivered glucose oxidase (GOx) acidified the local environment through glucose consumption, collectively amplifying oxidative stress. TRPML1 activation promoted Zn 2+ flux and ROS signaling to inhibit HIF‐1α activity, thereby suppressing GLUT1 and restricting glucose uptake. Consequently, NADPH/GSH regeneration was impaired, causing a collapse of reducing power and triggering disulfidptosis. Simultaneously, zinc overload and ROS cooperatively exacerbated lysosomal membrane damage, activated the NLRP3 inflammasome, and induced caspase‐1‐dependent pyroptosis. These dual death programs synergistically enhanced immunogenic cell death and further reversed the immunosuppressive tumor microenvironment. Together, this study establishes the TRPML1/HIF‐1α/GLUT1 axis as a critical pathway linking lysosomal zinc signaling to glucose‐metabolic vulnerability and provides a new therapeutic avenue for aggressive osteosarcoma.