Targeted Perturbation of Mitochondrial Energy Metabolism via Thermoelectric Nanoflowers for Enhanced Cuproptosis Echoed With Immunotherapy

ABSTRACT Cuproptosis, a novel anti‐cancer mechanism, holds significant potential for triggering sequential immunotherapy to enhance anti‐cancer efficacy. However, this cascade effect is often limited by copper efflux mechanisms mediated by the copper‐transporting ATPase (ATP7B), which reduces intracellular copper accumulation and negates cuproptosis. Here, we designed a mitochondria‐targeting thermoelectric nanoplatform to interfere with the electron transport chain (ETC) of mitochondria, causing adenosine triphosphate (ATP) outage to inhibit ATP7B function, thereby enhancing cuproptosis to achieve a synergistic immunotherapy effect. The nanoplatform was fabricated on a thermoelectric copper telluride (Cu 2‐x Te) base, doped with bismuth (Bi) to enhance its performance. The morphology was engineered into nanoflowers (NFs) to greatly expand its surface area, achieving a high photothermal conversion efficiency of 66.88%. The established temperature gradient drives a thermoelectric catalytic process on the material's surface, leading to the generation of substantial superoxide anion radicals (•O 2 − ) to oxidize mitochondrial nicotinamide adenine dinucleotide (NADH), interfering with ETC to impede ATP biosynthesis. We demonstrated that the NFs effectively potentiate cuproptosis and trigger robust immunotherapy, confirming their significant anti‐cancer efficacy both in vitro and in vivo. This study exemplifies a strategy to amplify tumor immunotherapy by enhancing cuproptosis through thermoelectric materials.