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

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 (Cu2-xTe) 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 (•O2 -) 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.