ALKBH1 drives codon-biased, pro-oncogenic translation and tumor microenvironment remodeling in glioma via tRNA wobble oxidation

Abstract

Gliomas rely on translational plasticity to sustain heterogeneity, stemness, and immune evasion. Here we identify the tRNA dioxygenase ALKBH1 as a central regulator of codon-biased translation and tumor microenvironment remodeling. LC-MS/MS profiling of patient tumors revealed enrichment of ALKBH1-mediated wobble cytidine oxidation modifications in high-grade gliomas. Genetic perturbation demonstrated that ALKBH1 overexpression slows proliferation in vitro but worsens survival in vivo by promoting glioma stem-like and neuronal states and suppressing anti-tumor immunity. Ribosome profiling showed that ALKBH1 establishes an A/T-ending codon-biased translational program, enhancing decoding of rare leucine codons (TTA/TTG) and driving synthesis of pro-stemness transcripts. Single-cell RNA-seq analyses further revealed that ALKBH1 promotes glioma heterogeneity and induces neuronal cell clusters and rewires intercellular communication ECM-related signaling while dampening immune pathways and reducing immune infiltration. These findings establish a mechanistic link between tRNA oxidation, codon bias, and glioma aggressiveness, positioning ALKBH1 as a potential therapeutic target for glioma.