Engineering an immuno-nanoprodrug: Photo-controlled pyroptosis synergizing with acid-activatable immunometabolic blockade for potent cancer immunotherapy

Although immunotherapy has revolutionized cancer treatment, antitumor immunological responses remain limited by insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. Herein, pyroptosis induction is integrated into a photosensitizer to potentiate tumor immunogenicity. In this part, artesunate is disclosed to increase GSDME and modified to synthesize its ROS-cleavable prodrug, which is then installed into the self-assembled photosensitizer, resulting in a novel oil-in-water nanoplatform (BDP-pATS). The cytotoxicity, pyroptosis feature and potentiated GSDME induced by BDP-pATS are well confirmed. Subsequently, a novel acid-activatable adenosine-A2AR inhibitor is synthesized and further installed into the aforementioned platform to obtain BDP-pATS-aA2Ai, manipulating immunometabolic strategy to counterbalance the enhanced adenosine caused by pyroptosis. Such a photo-controlled and acid-activatable nanoprodrug enhances cytotoxic T cell functions while restrains regulatory T cell activities, leading to potent effects toward primary and abscopal tumor inhibition. In addition, BDP-pATS-aA2Ai also manifests desirable performance on pulmonary metastasis and tumor recurrence mouse model. To the best of our knowledge, this study presents the first concept of blocking adenosine-A2AR pathway during pyroptosis occurrence. Collectively, this work strategically combines immunometabolic interception, pyroptosis induction, photodynamic therapy and epigenetic regulation, emphasizing the significance of comprehensive therapy, which should open up a new viewpoint for cancer immunotherapy.