The use of polyprodrugs, which bind drugs to polymer chains through responsive linkers, is a potential technique for cancer therapy; however, a lack of endogenous triggering factors limits drug activation in tumor tissue. Herein, we rationally created a reactive oxygen species (ROS)-sensitive polyprodrug (TSCA/DOX) with cascade amplification of triggering agents and drug activation by incorporating both an ROS signal amplifier (TACA) and a drug activation amplifier (SIPDOX) into a delivery system. Endogenous ROS as a triggering mechanism kicked off the initial circulation phase to increase intracellular ROS signals. Subsequently, the enhanced ROS initiated the second degradation step, allowing the polyprodrug SIPDOX to fracture spontaneously in a domino-like fashion, resulting in self-accelerated drug activation in tumor tissue. Therefore, the polyprodrug created in this study with cascade amplification of drug activation holds great promise for effective cancer treatment.