Chen Xiaoyong, Tang Xiangjun, Xie Ying, Cuffari Benedette J, Tang Caroline, Cao Fei, Gao Xingchun, Meng Zhouqi, Noble Philip W, Young Melissa R, Turk Olivia M, Shirali Anupama, Gera Joseph, Nishimura Robert N, Zhou Jiangbing, Hansen James E
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA.
Sci Signal. 2025 Mar 25;18(879):eadk3320. doi: 10.1126/scisignal.adk3320.
Nucleic acid-mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody entered cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and bound to endogenous RNA in live cells. In orthotopic models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on T cells. Mechanistic studies revealed that antibody binding to nucleic acids activated the cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody-nucleic acid interaction that is translatable to strategies for nonviral gene delivery and immunotherapy.
核酸介导的信号传导引发免疫反应，这种免疫反应被认为是系统性红斑狼疮（SLE）自身免疫病理生理学的核心。在此，我们发现一种可穿透细胞、与SLE相关的抗鸟苷自身抗体可能为癌症治疗提供治疗机会。该自身抗体通过一条与核苷补救相关的膜转运途径进入细胞，该途径避开内体和溶酶体，并与活细胞中的内源性RNA结合。在胶质母细胞瘤的原位模型中，该抗体定位于坏死肿瘤细胞附近区域，并以依赖T细胞的方式促进动物存活。机制研究表明，抗体与核酸的结合激活了细胞质模式识别受体环鸟苷酸-腺苷酸合成酶（cGAS），从而刺激免疫信号传导和cGAS依赖性细胞毒性。此外，当局部给药时，该自身抗体可以将功能性RNA携带并递送至活小鼠的肿瘤、脑和肌肉组织中。这些发现建立了一种可转化为非病毒基因递送和免疫治疗策略的自身抗体-核酸协同相互作用。
