A dual-lock strategy for tumor-specific pyroptosis activation plus gas synergism.

Pyroptosis, a canonical type of immunogenic cell death (ICD), has recently garnered extensive attention and become a highly promising strategy to enhance the efficacy of tumor immunotherapy. Unfortunately, current pyroptosis inducers face critical limitations in clinical practice, stemming from poor tumor selectivity, severe off-target effects, acquired resistance, and inadequate efficacy. Therefore, the precise induction of tumor cell pyroptosis is crucial for cancer immunotherapy, especially for the safe treatment of tumors. Herein, we designed and developed a small-molecule pyroptosis inducer (Cy-DNBS) synergistically activated by intratumoral overexpressed glutathione (GSH) and near-infrared (NIR) light. Upon GSH-triggered activation in tumors, Cy-DNBS generates fluorescence/photoacoustic (FL/PA) multimodal signals, owing to the suppression of photoinduced electron transfer (PET), and can subsequently produce large amounts of reactive oxygen species (ROS) through a photodynamic process. Meanwhile, SO2 released during activation further consumes GSH and amplifies the ROS storm, which ultimately triggers the caspase-3/GSDME-mediated pyroptosis pathway in tumor cells, remodels the immunosuppressive tumor microenvironment, and exerts potent therapeutic efficacy in tumor-bearing mouse models. This study not only exploits a new molecular platform for multimodal tumor theranostics, but also offers a safe and potent innovative strategy to precisely trigger tumor cell pyroptosis for high-efficiency cancer immunotherapy.