Stimuli-responsive nanoplatforms for precision activation of the STING pathway in cancer immunotherapy

The stimulator of interferon genes (STING) pathway plays a unique role in antitumor immunity, bridging innate and adaptive immune responses to initiate a sustained and highly effective antitumor immune response. However, due to the widespread expression of the STING pathway and the lack of clearly distinguishable physiological and pathological features, its excessive or systemic activation can trigger severe adverse effects, such as cytokine storms, thereby limiting its clinical applicability. With the development of nanotechnology, stimuli-responsive nanoplatforms designed based on tumor microenvironment (TME) signals (such as pH, glutathione, reactive oxygen species, hypoxia, and enzymes) and exogenous stimuli (including light, ultrasound, radiation, and magnetic fields) provide a promising strategy for the precise activation of the STING pathway. These nanoplatforms can achieve tumor-specific and controllable STING activation, thereby minimizing off-target toxicity, and can be combined with chemotherapy, radiotherapy, or photodynamic therapy to produce multimodal synergistic antitumor effects. Here, we provide a systematic overview of stimuli-responsive nanoplatforms for STING activation, highlighting their design strategies and how they can reverse immunosuppressive TME through STING pathway activation. Additionally, we discuss the challenges facing their clinical translation and outline future directions, aiming to provide a foundation for further research in this field. In conclusion, stimuli-responsive STING-activating nanoplatforms demonstrate significant potential in antitumor therapy and may serve as a novel therapeutic strategy.