In recent years, nanotechnology has been widely used in the field of tumor treatment. Some nanomedicine applications have been approved for tumor treatment, but nanomedicine has not so far demonstrated the anticipated therapeutic effect. In this process, the tumor microenvironment plays a major role. The tumor microenvironment is an internal environment that supports tumor occurrence, development, and metastasis. It is composed of tumor cells and related cells, intercellular substances, capillaries, and biomolecules that pervade both the tumor mass itself and its surrounding area. The tumor microenvironment can be a potential target for tumor treatment. Therefore, nano-antitumor therapy targeting the tumor microenvironment has received widespread attention. This therapy is based on the physiological characteristics of tumors that differ from those of normal tissues. The tumor microenvironment is used as a therapeutic target, and drugs are delivered to the tumor site through nanoparticles-enabled targeting to achieve fast, controllable, and efficient tumor killing. This article reviews basic research such as design principles and applications of nano-antitumor therapeutic strategies targeting the tumor microenvironment, providing a theoretical basis and new research ideas for tumor treatment.