Stimuli‐Responsive Hydrogels for Cancer Therapy: Design Strategies, Mechanisms, and Challenges in Clinical Translation

Stimuli-responsive hydrogels (SRHs) are versatile soft biomaterials capable of dynamically responding to environmental cues, enabling controlled and site-specific drug release for cancer therapy. Advances in polymer chemistry and nanotechnology have facilitated the development of SRHs that respond to tumor-associated stimuli, including pH, redox potential, temperature, enzymatic activity, light, and glucose gradients. Among these systems, pH- and redox-responsive hydrogels exploit the acidic and oxidative tumor microenvironment, while thermo- and photo-responsive platforms enable spatiotemporal regulation of therapeutic payloads. Recent studies have demonstrated highly efficient, stimulus-triggered drug release and enhanced therapeutic outcomes in vitro and in vivo. This review systematically examines the design strategies, molecular mechanisms, and structure-function relationships governing SRHs in oncology. Emerging hydrogel architectures-such as injectable systems, hybrid nanocomposites, and multifunctional platforms integrating targeting or imaging capabilities-are critically discussed. Importantly, the review addresses key challenges in clinical translation, including biocompatibility, scalability, regulatory considerations, and reproducibility. Finally, future perspectives are outlined, highlighting the potential of artificial intelligence-assisted material design, computational modeling, and wearable or implantable bioelectronic interfaces for real-time monitoring and adaptive cancer therapy. By integrating mechanistic insights with translational and regulatory viewpoints, this review aims to guide the rational development of next-generation smart hydrogel therapeutics for clinical oncology.