Hypoxia and nutrient deficiency trigger a protease, AEP, thus inducing precise cleavage of DDX3X, which dysregulates AS in a HIF1A-dependent manner, indicating that tumor microenvironment–regulated proteomic and transcriptomic heterogeneity can be achieved by precise protease substrate cleavage without genetic/epigenetic changes. This evidence concerns the gene HIF1A and neoplasm.