Sono‐Triggered Cascade Lactate Depletion by Semiconducting Polymer Nanoreactors for Cuproptosis‐Immunotherapy of Pancreatic Cancer

Abstract The high level of lactate in tumor microenvironment not only promotes tumor development and metastasis, but also induces immune escape, which often leads to failures of various tumor therapy strategies. We here report a sono‐triggered cascade lactate depletion strategy by using semiconducting polymer nanoreactors (SPN LCu ) for cancer cuproptosis‐immunotherapy. The SPN LCu mainly contain a semiconducting polymer as sonosensitizer, lactate oxidase (LOx) conjugated via a reactive oxygen species (ROS)‐cleavable linker and chelated Cu 2+ . Upon ultrasound (US) irradiation, the semiconducting polymer generates singlet oxygen ( 1 O 2 ) to cut ROS‐cleavable linker to allow the release of LOx that catalyzes lactate depletion to produce hydrogen peroxide (H 2 O 2 ). The Cu 2+ will be reduced to Cu + in tumor microenvironment, which reacts with the produced H 2 O 2 to obtain hydroxyl radical (⋅OH) that further improves LOx release via destroying ROS‐cleavable linkers. As such, sono‐triggered cascade release of LOx achieves effective lactate depletion, thus relieving immunosuppressive roles of lactate. Moreover, the toxic Cu + induces cuproptosis to cause immunogenic cell death (ICD) for activating antitumor immunological effect. SPN LCu are used to treat both subcutaneous and deep‐tissue orthotopic pancreatic cancer with observably enhanced efficacy in restricting the tumor growths. This study thus provides a precise and effective lactate depletion tactic for cancer therapy.