增加细胞免疫原性和重塑免疫肿瘤微环境(TME)对于抗肿瘤免疫治疗至关重要。在这里,我们开发了一种新型的单原子纳米酶解热引发剂:UK5099和丙酮酸氧化酶(POx)共负载的Cu-NS单原子纳米酶(Cu-NS@UK@POx),这不仅通过级联生物催化引发焦亡以增强肿瘤细胞的免疫原性,而且还通过靶向丙酮酸代谢来重塑免疫抑制性TME。通过用弱负电性S代替N,改变了原来Cu-N4电子分布的空间对称性,有效地调控了酶催化过程。与空间对称Cu-N4单原子纳米酶(Cu-N4SA)相比,S掺杂的空间非对称单原子纳米酶(Cu-NSSA)表现出更强的氧化酶活性,包括过氧化物酶(POD),烟酰胺腺嘌呤二核苷酸(NADH)氧化酶(NOx),L-半胱氨酸氧化酶(LCO)和谷胱甘肽氧化酶(GSHOx),这可能会导致足够的活性氧(ROS)风暴触发焦亡。此外,Cu-NSSA的协同作用,UK5099和POx可以靶向丙酮酸代谢,这不仅提高了免疫TME,而且增加了焦亡的程度。这项研究提供了一种双管齐下的治疗策略,可以通过ROS风暴显着激活抗肿瘤免疫治疗作用,NADH/谷胱甘肽/L-半胱氨酸消耗,丙酮酸氧化,和乳酸/ATP消耗,触发焦亡和调节新陈代谢。这项工作为扩大抗肿瘤免疫治疗提供了广阔的视野。本文受版权保护。保留所有权利。
Increasing cellular immunogenicity and reshaping the immune tumor microenvironment (TME) are crucial for antitumor immunotherapy. Herein, this work develops a novel single-atom nanozyme pyroptosis initiator: UK5099 and pyruvate oxidase (POx)-co-loaded Cu-NS single-atom nanozyme (Cu-NS@UK@POx), that not only trigger pyroptosis through cascade biocatalysis to boost the immunogenicity of tumor cells, but also remodel the immunosuppressive TME by targeting pyruvate metabolism. By replacing N with weakly electronegative S, the original spatial symmetry of the Cu-N4 electron distribution is changed and the enzyme-catalyzed process is effectively regulated. Compared to spatially symmetric Cu-N4 single-atom nanozymes (Cu-N4 SA), the S-doped spatially asymmetric single-atom nanozymes (Cu-NS SA) exhibit stronger oxidase activities, including peroxidase (POD), nicotinamide adenine dinucleotide (NADH) oxidase (NOx), L-cysteine oxidase (LCO), and glutathione oxidase (GSHOx), which can cause enough reactive oxygen species (ROS) storms to trigger pyroptosis. Moreover, the synergistic effect of Cu-NS SA, UK5099, and POx can target pyruvate metabolism, which not only improves the immune TME but also increases the degree of pyroptosis. This study provides a two-pronged treatment strategy that can significantly activate antitumor immunotherapy effects via ROS storms, NADH/glutathione/L-cysteine consumption, pyruvate oxidation, and lactic acid (LA)/ATP depletion, triggering pyroptosis and regulating metabolism. This work provides a broad vision for expanding antitumor immunotherapy.