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The abnormal pathophysiological characteristics of the tumor microenvironment, including acidosis, overexpression of special enzymes, hypoxia, and high levels of ROS, GSH, and ATP, offer the possibility for the design of stimulus-responsive DDSs for controlled drug release to realize more efficient drug delivery and anti-tumor activity. With the help of these stimulus signals, responsive DDSs can realize controlled drug release more precisely within the local tumor site and decrease the injected dose and systemic toxicity. This review first describes the major pathophysiological characteristics of the tumor microenvironment, and highlights the recent cutting-edge advances in DDSs responding to the tumor pathophysiological environment for cancer therapy. 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