Acid-Responsive Biocompatible Hydrogel Modulating Tumor DNA Self-Repair Collaborated with Chemotherapy for Boosting STING Pathway-Associated Immunotherapy

In this study, an acid-responsive hydrogel (ODCM@AZD) encapsulating doxorubicin (DOX), Mn2+, and AZD2281 is rationally engineered for synergistic chemo-immunotherapy. Notably, ODCM@AZD can be specifically degraded within the tumor microenvironment to release the loaded therapeutic agents. Specifically, the released DOX kills tumor cells to produce abundant cytoplasmic DNA, while the freed AZD2281 inhibits the DNA repair pathway of tumor cells to enhance the chemotherapeutic effect and promote the accumulation of damaged DNA, which is further aggravated by reactive oxygen species (ROS) generated from the Mn2+-mediated Fenton-like reaction. Not only that, Mn2+ simultaneously increases the sensitivity of cGAS to cytoplasmic DNA to stimulate the cGAS-STING pathway and synergizes with DOX-mediated immunogenic cell death (ICD) to initiate powerful antitumor immune responses. More importantly, the combination of ODCM@AZD with immune checkpoint blockade (ICB) significantly improves systemic tumoricidal immunity and potentiates therapeutic effects on distant and recurrent tumor models, providing a new idea for antitumor chemo-immunotherapy.