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.

Immuno-nanoprodrug  /  Immunometabolic blockade  /  Pyroptosis induction  /  Adenosine–A2AR  /  Photo-controlled  /  Acid-activatable  /  Cancer immunotherapy  /  Photoimmunotherapy