BackgroundLipid metabolic reprogramming has been increasingly recognized as a key factor contributing to tumor immune evasion, therapeutic resistance, and plasticity, which collectively compromise the efficacy of targeted radionuclide therapy (TRT). Overcoming the immunosuppressive and hypoxic tumor microenvironment (TME) while interfering with tumor lipid metabolism may offer a promising strategy to potentiate TRT outcomes.MethodsIn this report, a radiopharmaceutical with multienzymatic catalysis activities is developed, wherein tumor cell membrane-coated manganese single-atom nanozymes (Mn/SAE@M) as supports deliver iodine-131 (131I) to the tumor. The Mn/SAE nanozyme core was synthesized in situ within hollow mesoporous zeolitic imidazolate frame-8 (ZIF-8) nanoparticles, then coated with homologous tumor cell membranes for targeted delivery and subsequently labeled with 131I using the Chloramine-T method. A series of in vitro and in vivo experiments was performed in non-small cell lung cancer (NSCLC) models to evaluate therapeutic efficacy and immune activation.Results131I-Mn/SAE@M exhibited efficient tumor targeting and internalization mediated by membrane camouflage. Within the TME, the radiopharmaceuticals initiated abundant oxygen (O2) release through catalase (CAT)-like catalysis, thereby mitigating a hypoxic microenvironment. In particular, it produced and enriched more reactive oxygen species (ROS) through oxidase (OXD)-, peroxidase (POD)-, and glutathione oxidase (GSHOx)-like catalytic processes. Importantly, 131I-Mn/SAE@M activated the cGAS-STING pathway, interfered with the lipid metabolic homeostasis of tumor cells, and induced ferroptosis, which is unraveled to take responsibility for the potentiated antitumor immunity. In bilateral NSCLC tumor-bearing mice, the treatment suppressed both the first and the second tumors, indicating the generation of systemic antitumor immune responses and immunological memory.ConclusionsSuch SAE-based radiopharmaceuticals provide a candidate platform to elevate TRT efficiency, and the proof-of-concept rationale of disrupting lipid metabolic homeostasis through multienzyme-mimicking cascade reactions also provides a general avenue to improve TRT and synergistically magnify antitumor immunity.