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. Here, DDX3X is linked to neoplasm.