Abstract: The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, and metastasis. Its distinct biochemical features—such as high redox activity, elevated reactive oxygen species (ROS), acidity, hypoxia, and immunosuppression—not only promote tumor malignancy but also offer therapeutic targets. Recently, intelligent TME-responsive or TME-modulating nanodelivery systems have shown great potential in controlled drug release, immune activation, and synergistic multimodal therapy. Metal-organic frameworks (MOFs), as tunable porous hybrid nanomaterials with high surface areas, adjustable porosity, and facile surface modification, are ideal platforms for smart antitumor delivery. This review summarizes common MOF types and focuses on design strategies of MOF-based nanocarriers for modulating oxidative, acidic, hypoxic, and immunosuppressive TME, aiming to guide the development of more effective and safe MOF-based cancer therapies.