In this study, we demonstrate that arginine depletion when combined with IR is a highly effective therapeutic strategy in non-arginine-auxotrophic (ASS1-positive) GBM and we present evidence that the ability of ADI-PEG20 to potentiate the effects of radiation occurs predominantly via  ̇NO production and its effects on the TME, specifically by driving changes in the GAMM population toward a tumor-suppressing phenotype. This evidence concerns the gene ASS1 and neoplasm.