Biomimetic nanozyme reverse the Warburg effect to empower intrahepatic cholangiocarcinoma immunotherapy

Intrahepatic cholangiocarcinoma (ICC) is notoriously resistant to treatment, largely due to a "cold" microenvironment shaped by the Warburg effect. This metabolic signature leads to excessive lactate buildup, which acts as a physical and chemical shield against T-cell infiltration. To breach this barrier, we developed ultrasound-activated GdMnO₃ (GMO) perovskite nanozymes that forcibly reverse the Warburg effect by accelerating the lactate-to-pyruvate metabolic switch. Through Gd-incorporating, we optimized the Mn-based electronic structure to achieve high-efficiency lactate catabolism, which is pulsed by ultrasound to maximize enzymatic turnover. This intervention does not merely deplete lactate; it reshapes the tumor's "bioenergetic engine" from glycolytic acidification toward mitochondrial oxidation. When cloaked in M1 macrophage membranes (GMO@M), these nanozymes selectively accumulate in ICC tissues. The subsequent Mn²⁺ release triggers the cGAS-STING pathway, synergizing with the metabolic shift to flip the immunological status of the tumor. Combined with αPD-L1, this ultrasound-driven metabolic recalibration yields potent systemic immunity and durable tumor regression. Our findings demonstrate that targeting the Warburg effect via responsive nanozymes is a decisive strategy for sensitizing recalcitrant ICC to immunotherapy.