AbstractSonodynamic therapy (SDT) is a rapidly developing, safe, and noninvasive method for tumor treatment. SDT relies on ultrasound to stimulate the activity of sonosensitizers, induce the production of many reactive oxygen species (ROS), and mediate tumor cell death. The complex tumor microenvironment (TME) is the basis of tumorigenesis and tumor development. The characteristics of the TME, which are different from those of normal tissue, are essential factors in regulating the response to antitumor therapy. The therapeutic effect of SDT is affected by the TME. Therefore, the study of multifunctional sonosensitizers related to the TME is a future direction to enhance the efficacy of SDT in treating tumors. This review summarizes the characteristics of the TME, the factors that regulate it, and its role in regulating the response to sonosensitizers. It introduces strategies for enhancing the therapeutic effect of SDT by exploiting the TME and highlights the prospects of combination therapy for tumors based on the characteristics of the TME. With this paper, it is hoped to provide a research direction for improving the therapeutic effect of SDT and promoting its clinical translation in the future.