Cancer remains one of the most severe global health challenges. The emergence of nanomedicines has opened new avenues for targeted tumor therapy, with over 15 types currently in clinical use. Although nanomedicines improve drug accumulation through the enhanced permeability and retention effect, challenges such as inefficient and nonspecific drug release limit their therapeutic efficacy. Due to abnormal proliferation and metabolic disorders, the tumor microenvironment (TME) exhibits significant differences from normal tissues, including low pH, hypoxia, and enzyme overexpression. These specific endogenous signals provide opportunities to achieve tumor-specific drug release and enhance the therapeutic effect of cancer treatment. Consequently, TME-responsive nanomedicines have garnered significant attention from researchers. This review systematically summarizes the latest advancements in TME-responsive nanomedicines in recent years. Furthermore, we discuss several emerging challenges and prospects of TME-responsive nanomedicines, aiming to provide novel insights and significant breakthroughs in this field.