PO.CL05.08 · 临床研究
通过生物电磁重编程肿瘤-免疫代谢以选择性摧毁NSCLC
Bioelectromagnetic reprogramming of tumor-immune metabolism to selectively destroy NSCLC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：氧和氧化还原活性金属代谢失调在非小细胞肺癌（NSCLC）中造成了氧化性肿瘤微环境。肿瘤积累活性氧（ROS）和不稳定铁，促进进展，但也造成了对铁催化的ROS和脂质过氧化的易感性。这种氧化性微环境还改变了肿瘤-免疫代谢平衡，阻碍TME中的免疫功能。现有的基于电磁的疗法（如肿瘤治疗电场和电穿孔）不直接靶向氧化还原-代谢易感性，且存在可用性限制。基于我们最近发表于Cell Metabolism的研究——正交施加的静态电磁场（EMF）可安全地重编程氧化还原和葡萄糖代谢以治疗糖尿病，我们试图确定在便捷的治疗时段内施加的生物电磁模式是否可被设计用于重编程肿瘤-免疫代谢，从而选择性杀伤NSCLC。
方法：我们设计了一种装置，以每天≥6小时递送正交取向的静态EMF。荷有人NSCLC异种移植瘤（H1299和A549）或同基因LLC肿瘤的小鼠被随机分为EMF组或假处理组。评估了肿瘤生长、生存以及与放化疗的联合。机制研究评估了脂质过氧化、gammaH2AX、T细胞活化/耗竭以及抗原特异性CD8⁺的迁移、CD4⁺/CD8⁺清除，以及清除H₂O₂、不稳定铁或脂质过氧化物对铁死亡途径的影响。组织病理学评估了毒性。
结果：EMF单药治疗相较于假处理抑制了肿瘤生长并延长了生存，并改善了放化疗疗效。EMF治疗的肿瘤显示脂质过氧化物和gammaH2AX增加，与脂质过氧化和DNA损伤诱导的肿瘤死亡一致。在同基因肿瘤中，EMF增强了CD8⁺和CD4⁺ T细胞活化并减少了耗竭。OT-I和T细胞清除研究表明EMF疗效需要抗原特异性适应性免疫。在肿瘤内对H₂O₂、铁或脂质过氧化物进行遗传性清除减弱了EMF诱导的肿瘤杀伤，证明了铁死亡性肿瘤死亡且无正常组织毒性。
结论：正交施加的静态EMF代表了一种新型生物电子策略，通过利用氧化还原-代谢易感性并激活抗肿瘤免疫来选择性杀伤NSCLC。这种生物电子模式可用于安全地增强肿瘤杀伤，同时克服现有基于电场模式的依从性挑战。
查看英文原文 English abstract
BACKGROUND: Dysregulated oxygen and redox-active metal metabolism create an oxidized tumor microenvironment in non-small cell lung cancer (NSCLC). Tumors accumulate reactive oxygen species (ROS) and labile iron, promoting progression yet creating a vulnerability to iron-catalyzed ROS and lipid peroxidation. This oxidized microenvironment also alters tumor-immune metabolic balance, impeding immune function in the TME. Existing electromagnetic-based therapies such as tumor treating fields and electroporation do not directly target redox-metabolic vulnerabilities and have usability constraints. Building on our recent work published in Cell Metabolism showing that orthogonally applied static electromagnetic fields (EMFs) safely reprogram redox and glucose metabolism to treat diabetes, we sought to determine whether a bioelectromagnetic modality applied during convenient treatment times could be engineered to reprogram tumor-immune metabolism for selective killing of NSCLC.
METHODS: We engineered a device to deliver orthogonally oriented static EMFs for ≥6 hours / day. Mice bearing human NSCLC xenografts (H1299 & A549) or syngeneic LLC tumors were randomized to EMF or sham. Tumor growth, survival & combination with chemoradiation therapies were evaluated. Mechanistic studies assessed lipid peroxidation, gammaH2AX, T-cell activation/exhaustion & antigen-specific CD8⁺ trafficking, CD4⁺/CD8⁺ depletion, and effects of scavenging H₂O₂, labile iron, or lipid peroxides on ferroptotic pathways. Histopathology assessed toxicity.
RESULTS: EMF monotherapy inhibited tumor growth & prolonged survival versus sham and improved chemoradiation efficacy. EMF-treated tumors showed increased lipid peroxides and gammaH2AX, consistent with lipid peroxidation and DNA damage induced tumor death. In syngeneic tumors, EMF enhanced CD8⁺ and CD4⁺ T-cell activation and reduced exhaustion. OT-I and T-cell depletion studies showed EMF efficacy requires antigen-specific adaptive immunity. Genetic scavenging of H₂O₂, iron, or lipid peroxides within tumors attenuated EMF-induced tumor killing, demonstrating ferroptotic tumor death without normal-tissue toxicity.
CONCLUSIONS: Orthogonally applied static EMFs represent a novel bioelectronic strategy to selectively kill NSCLC by exploiting redox-metabolic vulnerabilities and activating antitumor immunity. This bioelectronic modality could be used to safely enhance tumor killing while overcoming adherence challenges of existing field-based modalities.
利益披露 Disclosure
S. Huang,
Geminii, Inc. g., Board of Directors, non-salaried role), Stock, Travel, Patent.
J. Petssche, None..
D. Foster, None..
C. Searby, None..
V. Sheffield, None.
C. Carter,
Geminii, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Travel, Patent.