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. 2025 Mar 25;18(879):eadk3320.
doi: 10.1126/scisignal.adk3320. Epub 2025 Mar 25.

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells

Xiaoyong Chen  1 , Xiangjun Tang  2 , Ying Xie  2 , Benedette J Cuffari  1 , Caroline Tang  1 , Fei Cao  1 , Xingchun Gao  2 , Zhouqi Meng  2 , Philip W Noble  1 , Melissa R Young  1   3 , Olivia M Turk  1 , Anupama Shirali  1 , Joseph Gera  4   5   6   7 , Robert N Nishimura  7   8 , Jiangbing Zhou  2   3 , James E Hansen  1   3
Affiliations

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells

Xiaoyong Chen et al. Sci Signal. .

Abstract

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.

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Conflict of interest statement

X.C., Y.X., B.J.C., C.T., P.W.N., M.R.Y., A.S., J.Z., and J.E.H. are inventors on patent filings by Yale University pertaining to the use of anti-DNA autoantibodies in molecular therapy. Yale University has filed patents, with inventors J.E.H., J.Z., X.C., Y.X., “Compositions and methods for modulating cGAS” and “Compositions and methods for delivery of nucleic acids to cells.” J.Z. and J.E.H. have equity/option interest in, receive grant support from, and consulted for Patrys Ltd. J.Z. is co-founder and chief technology adviser for Couragene. The other authors declare that they have no competing interests.

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