<p>Pyroptosis induces the release of elevated levels of damage-associated molecular patterns (DAMPs) and holds significant potential for therapeutic applications. However, existing strategies for inducing pyroptosis are constrained by rapid clearance, potential off-target toxicity, and the challenges posed by the aberrant tumor microenvironment (TME). Therefore, this work introduces a nanozyme-based pyroptosis amplifier (NPA), formed by integrating Cu₂O@Au nanozymes and the H₂S-releasing agent (NH₄)₂S into an injectable hydrogel matrix. The developed system responds to near-infrared (NIR) laser, disrupting multiple homeostatic mechanisms in tumor cells while inducing gas therapy and enhanced pyroptosis. Upon intratumoral injection, NPA experienced thermal softening under 808&#xa0;nm laser irradiation, enabling localized mild photothermal therapy and simultaneous release of Cu₂O@Au nanozymes and (NH₄)₂S. Cu₂O@Au nanoparticles catalyzed the oxidation of glucose, resulting in H₂O₂ generation, energy depletion, and acidification of the TME. These changes enhanced the Cu⁺-mediated Fenton-like reaction, generating reactive oxygen species (ROS) and activates the NLRP3 and GSDMD pathway to induce pyroptosis. Furthermore, the acidified microenvironment and elevated temperature synergistically trigger H₂S release, leading to mitochondrial disruption and further amplifying pyroptosis. Overall, the precise in situ regulation of the hydrogel system significantly enhances pyroptosis induced by nanomedicines, offering valuable insights into cancer treatment strategies. This hydrogel-mediated photoinduced pyroptosis system introduces a novel approach to cancer therapy, paving the way for innovative therapeutic approaches.</p> Graphical Abstract <p></p>