Self-sustaining ROS-responsive hydrogel enabled delivery of PROTAC/Ce6 nanoparticles via PDT-Epigenetic protein degradation to amplify pyroptosis for enhanced cancer immunotherapy.

Cancer immunotherapy exhibits limited efficacy in immunologically "cold" tumors due to insufficient T-cell infiltration and immunosuppressive tumor microenvironment. The efficacy of photodynamic therapy (PDT) is restricted by inadequate tumor-specific aggregation of photosensitizers and therapeutic resistance regulated by epigenetics. Herein, we engineered a light-driven, ROS-responsive hydrogel (PACL@Gel) for loading peptide-lipid scaffold nanoparticles encapsulating proteolysis targeting chimera (PROTAC) molecule and photosensitizer to enhance cancer immunotherapy. The system utilizes both endogenous and photodynamically amplified ROS to drive controlled hydrogel degradation and nanoparticle release, establishing a self-sustaining ROS feedback loop to overcome the limitations of insufficient endogenous ROS. The released PACL nanoparticles synergistically combine PDT with epigenetic BRD4 protein degradation to robustly amplify Caspase-3/GSDME dependent pyroptosis. Pyroptotic tumor cells would trigger immunogenic cell death, releasing inflammatory mediators and damage-associated molecular patterns that promote dendritic cells maturation and T-cell activation and infiltration to effectively remodel the immunosuppressive tumor niche and promote antitumor immunity. Experimental results validated that under laser irradiation, PACL@Gel demonstrated potent local tumor suppression and distant abscopal effect, prevented postoperative recurrence and established long-term immune memory. Collectively, this integrated PROTAC-PDT hydrogel platform effectively reprograms the immunosuppressive tumor microenvironment, providing a robust and actionable approach to enhance PDT therapy in immunologically cold tumors combined with epigenetic strategies.