Hypoxia is a feature of the tumor microenvironment (TME), which is closely associated with tumor invasion and drug resistance. It has been confirmed that alleviating tumor hypoxia is a crucial strategy for enhancing the tumor treatment efficacy. With the development of nanomedicine, stimulus-responsive nanomedicine delivery systems (NDDS) with the ability to reshape the TME have attracted significant attention. These NDDS typically consist of stimulus-responsive frameworks and cargo. They remain stable under normal physiological conditions and release their cargo only upon specific stimuli, such as acidic pH or high GSH levels. In addition to stimuli in the TME, numerous external stimuli have been used to activate the NDDS in recent years, such as thermal, near-infrared light and ultrasound. Unlike previous reviews, we integrate internal and external stimulus-responsive strategies with hypoxia-alleviating mechanisms to guide the rational design of novel nanosystems. Furthermore, we highlight emerging multi-stimulus-responsive platforms, with particular emphasis on their potential for precise control and clinical translation.
