Cancer cells are intrinsically addicted to glucose and require glucose transporter 1 (GLUT1)-mediated glucose metabolism for their survival. Although small-molecule inhibitors of GLUT1 have exhibited suppressive effects on tumor cells, they achieve only transient functional blockade, thereby limiting therapeutic durability and permitting metabolic escape. Here, we report MetaTAC-G1, an mRNA-encoded lysosome-targeting chimera that enables rapid and sustained degradation of cell-surface GLUT1. MetaTAC-G1 comprises a bispecific binder that bridges GLUT1 to the lysosomal trafficking receptor sortilin, thereby directing constitutive lysosomal clearance of the transporter upon translation. For local intratumoral delivery, we encapsulated the MetaTAC-G1-encoding mRNA in RGD-functionalized lipid nanoparticles (RGD-LNPs), achieving efficient mRNA expression and sustained GLUT1 degradation. Functionally, MetaTAC-G1 induced profound metabolic collapse in SUM159PT cells, characterized by acute ATP depletion and reactive oxygen species (ROS) accumulation, culminating in GSDMD-dependent pyroptosis. Similar pyroptosis-associated morphological changes were observed across multiple additional cancer cell lines. In vivo, a single treatment course of MetaTAC-G1 markedly suppressed tumor growth and produced durable antitumor activity without apparent systemic toxicity. Our findings highlight that sustained degradation of GLUT1, rather than transient functional inhibition, is critical for triggering metabolic cell death in tumors.
