p53/cGAS/STING pathway

Overview

The p53/cGAS/STING pathway represents a convergent signaling axis linking cellular stress responses, DNA damage sensing, and innate immune activation. At its core, the pathway integrates two major surveillance systems: the tumor suppressor protein TP53, which orchestrates cell cycle arrest, apoptosis, and senescence in response to genomic instability, and the cGAS–STING (cyclic GMP-AMP synthase–Stimulator of Interferon Genes, encoded by STING1) innate immune sensing cascade, which detects cytosolic DNA and triggers type I interferon and pro-inflammatory cytokine production. When cellular stress or DNA damage accumulates — whether from genotoxic agents, oxidative insult, or pathological conditions — TP53 activation can promote micronuclei formation and cytosolic DNA release, providing ligands that engage cGAS. The resulting second messenger cGAMP then activates STING1, driving downstream transcriptional responses including NF-κB and IRF3-mediated interferon signaling. This coupling between tumor suppression and innate immunity makes the p53/cGAS/STING pathway a central node in cancer immunosurveillance, neuroinflammation, and fibrotic disease.

The biological significance of this pathway extends across multiple disease contexts. In oncology, its activation can potentiate antitumor immunity by reprogramming the tumor microenvironment, and its dysregulation contributes to immune evasion. In neurological conditions, aberrant pathway activity drives neuroinflammation that underlies vascular and neurodegenerative pathologies. In pulmonary biology, STING1 signaling — particularly within alveolar macrophages — has been identified as a critical driver of fibrotic remodeling. These diverse roles have made the p53/cGAS/STING axis an increasingly attractive therapeutic target across oncology, neurology, and inflammatory disease.

Focus of Latest Publications

Recent publications have explored the p53/cGAS/STING pathway across diverse therapeutic contexts, revealing divergent strategies for pathway modulation depending on disease type. In cancer, STING pathway activation has become a central immunotherapeutic approach, with multiple nanomedicine platforms designed to synergistically activate STING signaling and innate immunity to convert immunologically "cold" tumors into immunologically "hot" tumors. Carrier-free nanoparticles combining STING agonists with photodynamic therapy agents demonstrated enhanced CD8+ T-cell infiltration and control of both primary and distant tumors in breast cancer, while piezoelectric nanocubes activated parallel pyroptosis-apoptosis-necroptosis and STING signaling in hepatocellular carcinoma. Additional therapeutic vehicles for STING activation included conjugates of STING agonists with immunomodulatory polysaccharides for pancreatic cancer immunotherapy, pH-responsive fusogenic liposomes for spatially confined pathway activation, and manganese-modified nanoemulsions carrying mRNA vaccines, each demonstrating superior efficacy to conventional delivery platforms.

Conversely, in chronic non-malignant pathologies, pathway inhibition emerged as the therapeutic strategy. In metabolic bone disease, the gut microbiota-derived metabolite TMAO activated cGAS-STING-mediated release of mitochondrial DNA and NF-κB signaling, driving osteoblast senescence and age-related bone loss; STING knockdown partially reversed this phenotype both in vitro and in vivo. In chronic pulmonary diseases, GAMG, an active metabolite of glycyrrhizin, directly bound STING and suppressed the downstream STING/TBK1/NF-κB cascade, reducing pro-inflammatory cytokines and pro-fibrotic responses in silicosis. In psoriasis, a traditional Chinese medicine formulation (YXKL) specifically inhibited STING/NF-κB signaling through identified flavonoid components quercetin and kaempferol, which bound STING and simultaneously suppressed cutaneous inflammation and abnormal vascular remodeling. STING pathway inhibition also benefited diabetic retinopathy, where elevated cytoplasmic dsDNA and cGAS-STING activation in retinal pigment epithelium cells drove inflammatory dysfunction; pharmacological STING inhibition reduced dsDNA accumulation and ameliorated retinal pathology in vivo.

Regulatory mechanisms governing STING protein stability and signaling activity were also elucidated. In clear cell renal cell carcinoma, the E3 ubiquitin ligase coactivator CDH1 stabilized STING through a non-canonical mechanism by binding to STING's destruction-box motif and sterically preventing association with the E3 ubiquitin ligase SPOP, thereby enhancing STING abundance and signaling upon pathway stimulation. Direct targeting of STING1 through inhalable lipid nanoparticles delivering CRISPR-Cas9 components achieved macrophage-specific gene disruption in idiopathic pulmonary fibrosis, successfully suppressing downstream STING signaling and reducing pro-fibrotic cytokine secretion. Emerging evidence also indicates integration of p53 regulation with cGAS-STING signaling in neuroinflammatory conditions, with traditional Chinese medicine formulations proposed to alleviate vascular cognitive impairment through modulation of the p53/cGAS/STING pathway axis.