Xiang Qinyanqiu, Yang Xue, Zhang Zhiqi, Yang Jie, Li Yingbo, Du Jiawei, Wang Jue, Fan Kai, Yuan Jiaxin, Zhang Jianqiong, Xie Jinbing, Ju Shenghong
Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 DingJiaQiao Road, Nanjing, 210009, P. R. China.
Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, 210009, P. R. China.
Adv Mater. 2025 Feb;37(8):e2419120. doi: 10.1002/adma.202419120. Epub 2025 Jan 6.
Immunogenic cell death (ICD)-mediated immunization strategies have great potential against breast cancer. However, traditional strategies neglect the increase in the immunosuppressive metabolite, adenosine (ADO), during ICD, leading to insufficient therapeutic outcomes. In this study, it is found that the adenosine A2A receptor (A2AR) is significantly expressed in breast cancer and positively associated with regulatory T (Treg) cells. Herein, a strategy combining Fe/Mo-based lipid peroxidation (LPO) nanoamplifiers and A2AR blockade is reported to maximize ICD-mediated anti-tumor immunity. This LPO nanoamplifier causes LPO explosion by the Fe (II)-mediated Fenton reaction and Mo(V)-mediated Russell mechanism. Subsequently, it elicits the ICD magnification of tumor cells by inducing multiple regulated cell death patterns of ferroptosis, apoptosis, and necroptosis. Additionally, the A2AR antagonist (SCH58261), an immunometabolic checkpoint blocker, is found to relieve ADO-related immunosuppression, amplify anti-tumor immunological effects, and elicit immune memory responses. This robust anti-tumor immunity is observed in primary, distant, pulmonary metastatic, and recurrent tumors. This study provides a novel strategy for optimizing ICD-mediated immunotherapy and highlights the benefits of combining LPO explosion with A2AR blockade to enhance breast cancer immunotherapy.
免疫原性细胞死亡（ICD）介导的免疫策略在对抗乳腺癌方面具有巨大潜力。然而，传统策略忽视了ICD过程中免疫抑制代谢物腺苷（ADO）的增加，导致治疗效果不佳。在本研究中，发现腺苷A2A受体（A2AR）在乳腺癌中显著表达，并与调节性T（Treg）细胞呈正相关。在此，报道了一种将铁/钼基脂质过氧化（LPO）纳米放大器与A2AR阻断相结合的策略，以最大化ICD介导的抗肿瘤免疫力。这种LPO纳米放大器通过铁（II）介导的芬顿反应和钼（V）介导的拉塞尔机制引发LPO爆炸。随后，它通过诱导铁死亡、凋亡和坏死性凋亡等多种调节性细胞死亡模式，引发肿瘤细胞的ICD放大。此外，发现A2AR拮抗剂（SCH58261），一种免疫代谢检查点阻滞剂，可缓解与ADO相关的免疫抑制，放大抗肿瘤免疫效应，并引发免疫记忆反应。在原发性、远处、肺转移性和复发性肿瘤中均观察到这种强大的抗肿瘤免疫力。本研究为优化ICD介导的免疫治疗提供了一种新策略，并强调了将LPO爆炸与A2AR阻断相结合以增强乳腺癌免疫治疗的益处。
