In Situ Formed ROS‐Responsive Hydrogel with STING Agonist and Gemcitabine to Intensify Immunotherapy against Pancreatic Ductal Adenocarcinoma

Abstract Immunotherapy, the most revolutionary anticancer strategy, faces major obstacles in yielding desirable outcomes in pancreatic ductal adenocarcinoma (PDAC) due to the highly immunosuppressive tumor microenvironment (TME). Meanwhile, when used alone, the traditional first‐line chemotherapeutic agent gemcitabine (GEM) in PDAC treatment is also insufficient to achieve lasting efficacy. In this study, a reactive oxygen species degradable hydrogel system, denoted as GEM‐STING@Gel, is engineered to codeliver gemcitabine and the stimulator of interferon genes (STING) agonist DMXAA (5,6‐dimethylxanthenone‐4‐acetic acid) into the tumor site. In this work, the strategy addresses the major challenges of current immunotherapies with a facile platform, which can synergistically activate innate immunity and promote the cytotoxic T lymphocytes infiltration at the tumor site, thereby modulating the immunosuppressive TME. Further, the efficient therapeutic potency of the immunotherapy is confirmed in an orthotopic postsurgical model, unleashing the translational potential to prevent tumor recurrence after surgical resection. This study underscores the advantages of this integrative strategy that combines chemotherapy, immunotherapy, and biomaterial‐based hydrogel, including improved therapeutic efficacy, operational convenience, and superior biosafety.