The amplification of reactive oxygen species (ROS) generation and glutathione (GSH) depletion in cancer cells represents a promising strategy to disrupt redox homeostasis for cancer therapy. Quinone methide and its analogs (QM) have recently been recognized as potential GSH scavengers for anticancer applications; however, an effective QM prodrug is yet to be developed. In this study, we prepare a self-immolative polymeric prodrug (SPP), which could be selectively degraded to generate large quantities of QMs in cancer cells during the spontaneous stepwise head-to-tail degradation of SPP. The amphiphilic SPP is self-assembled into nano-sized micelles, allowing for encapsulating 2-methoxy-β-estradiol (2ME), an anticancer drug that produces a large amount of intracellular ROS. When SPP@2ME, as the cascade-amplified prodrug, is treated on the cancer cells, 2ME is rapidly released at the ROS-rich intracellular environment by degradation of SPP, thus generating more ROS that triggers the degradation of more SPP chains. Such a domino-like cascade-amplified feedback loop significantly amplifies oxidative stress and disrupts the redox homeostasis in cancer cells. This unique strategy provides synergistic anticancer therapeutic efficacy and demonstrates an important perception in innovative and precise nanomedicine.