Nucleic acid-mediated signaling

• A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells
• Activated STAT3 regulates hypoxia-induced angiogenesis and cell migration in human glioblastoma

Nucleic acid-mediated signalling refers to cellular signaling pathways that are triggered by DNA or RNA molecules, especially when these nucleic acids are found in unusual locations or come from foreign sources (like viruses or damaged cells). These molecules serve as danger signals, activating the immune system or stress responses.

This type of signaling plays a critical role in innate immunity, allowing cells to detect infections, cancer, or tissue damage. It's also involved in autoimmune diseases, where the immune system mistakenly reacts to the body's nucleic acids.

1. Toll-like receptors (TLRs)

- TLR3: detects double-stranded RNA (dsRNA)

- TLR7/8: detect single-stranded RNA (ssRNA)

- TLR9: detects unmethylated CpG DNA (common in bacteria/viruses)

2. RIG-I-like receptors (RLRs)

- RIG-I and MDA5: detect viral RNA in the cytosol - Trigger antiviral responses via type I interferons

3. cGAS-STING pathway

- cGAS detects cytosolic DNA

- Activates STING, leading to production of interferons and inflammatory cytokines

4. AIM2 inflammasome

- Binds cytosolic DNA

- Triggers inflammation through caspase-1 and IL-1β production

- Viral infections (e.g., influenza, COVID-19)

- Cancer (cells release DNA into cytosol → immune detection)

- Autoimmune diseases (e.g., lupus: response to self-DNA/RNA)

- Therapeutic targets (STING agonists in cancer immunotherapy)

Nucleic acid-mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Chen et al. found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody enters cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and is 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), stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into the 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 ¹⁾.

Chen et al. deliver a conceptually bold and technically strong paper that bridges autoimmunity, cancer immunology, and gene delivery. While safety and specificity concerns remain, their discovery of a naturally evolved intracellular delivery vehicle opens new avenues for nonviral gene therapy and immune activation strategies.

High novelty, solid mechanistic insight, and strong translational potential, pending validation of safety and delivery scope.