In this study, we designed adenoviruses to deliver short hairpin RNAs (shRNAs) for TGF-β1 or TGF-β2 and found that downregulation of TGF-β1 or TGF-β2 leads to tumor cell death by inducing ASK1 activation and p38 and JNK phosphorylation through an ER stress/ROS-escalated positive feedback circuit. Here, MAP3K5 is linked to neoplasm.