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

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.