Injectable hydrogel-mediated spermidine delivery triggers tumor pyroptosis via oxidative metabolism for enhanced cancer therapy.

Intracellular polyamine metabolic homeostasis is closely linked to therapeutic outcomes in cancer. However, their intrinsic antitumor mechanisms have not been fully clarified. Herein, we demonstrate that the catabolism of spermine (Spm) and spermidine (Spd) mediated by polyamine oxidase directly generates two potent cytotoxic metabolites, namely acrolein and hydrogen peroxide. These metabolites act synergistically to trigger a marked elevation in intracellular reactive oxygen species (ROS), which in turn activate the caspase-1/GSDMD and caspase-3/GSDME signaling pathways, ultimately driving tumor cells into pyroptosis. Based on these findings, we develop a phenylboronic acid-functionalized sodium alginate-based hydrogel controlled-release system (Alg-PBA/Spd). This platform achieves sustained Spd release through coordination interactions and markedly inhibits tumor growth by inducing pyroptosis. Further studies demonstrate that the Alg-PBA/Spd hydrogel synergizes with radiotherapy (RT) to enhance radiosensitivity in an orthotopic breast cancer model and inhibit pulmonary metastasis. Moreover, this hydrogel enables co-delivery of αPD-L1 with sustained release, which significantly improves the response rate of immune checkpoint blockade therapy by inducing pyroptosis and remodeling the tumor immune microenvironment. Overall, this study not only elucidates a previously unrecognized mechanism underlying polyamine metabolism-driven pyroptosis but also offers a versatile platform to enhance the efficacy of RT and immunotherapy.