Cancer treatment is currently one of the most critical healthcare issues globally. A well-designed drug delivery system can precisely target tumor tissues, improve efficacy, and reduce damage to normal tissues. Stimuli-responsive drug delivery systems (SRDDSs) have shown promising application prospects. Intelligent nano drug delivery systems responsive to endogenous stimuli such as weak acidity, complex redox characteristics, hypoxia, active energy metabolism, as well as exogenous stimuli like high temperature, light, pressure, and magnetic fields are increasingly being applied in chemotherapy, radiotherapy, photothermal therapy, photodynamic therapy, and various other anticancer approaches. Metal-organic frameworks (MOFs) have become promising candidate materials for constructing SRDDSs due to their large surface area, tunable porosity and structure, ease of synthesis and modification, and good biocompatibility. This paper reviews the application of MOF-based SRDDSs in various modes of cancer therapy. It summarizes the key aspects, including the classification, synthesis, modifications, drug loading modes, stimuli-responsive mechanisms, and their roles in different cancer treatment modalities. Furthermore, we address the current challenges and summarize the potential applications of artificial intelligence in MOF synthesis. Finally, we propose strategies to enhance the efficacy and safety of MOF-based SRDDSs, ultimately aiming at facilitating their clinical translation.© 2025. The Author(s).