<p>Self-immolative polymers (SIPs) have recently emerged as a distinct class of stimuli-responsive materials that undergo programmed domino-like degradation in response to specific biochemical triggers. The unique biochemical characteristics of the tumor microenvironment (TME) include acidic pH, elevated glutathione (GSH) levels, excessive reactive oxygen species (ROS), dysregulated enzymes, and hypoxia. TME-responsive SIPs have attracted significant attention for precise cancer imaging and therapy. By integrating labile linkages and modular structural design, these polymers can amplify weak biochemical signals into robust responses, enabling controlled drug release, signal amplification in imaging, and multifunctional theranostics. Compared with conventional responsive systems, SIP-based nanoplatforms offer enhanced sensitivity, tunable degradation kinetics, and the potential for sequential or cascade activation. In this review, we provide a comprehensive overview of the design principles, activation mechanisms, and functional applications of TME-responsive SIPs. We highlight representative strategies for their use in targeted drug delivery, tumor imaging, and synergistic therapeutic approaches and discuss the incorporation of emerging modalities such as near-infrared II (NIR-II) imaging and combination immunotherapy. Finally, we outline the major challenges and opportunities for advancing SIP-based nanomedicines for clinical translation and offer perspectives on how this rapidly evolving field may reshape the future of precision cancer diagnosis and treatment.</p>