Review
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide, highlighting the need for novel therapeutic approaches. Inflammation plays a key role in CVD pathogenesis, and accumulating evidence has implicated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway in this process. The cGAS/STING pathway recognizes both non-self- and self-DNA, including mitochondrial and nuclear DNA, to activate its downstream proinflammatory signaling molecules, including TANK-binding kinase 1, IFN regulatory factor 3, and NF-κB. Various pathological stressors have been shown to induce self-DNA release into the cytosol and bloodstream from damaged cells in the cardiovascular system, indicating that circulating cell-free DNA is a useful biomarker of CVDs; however, how this contributes to the inflammatory signaling, cell death, and fibrosis that characterize CVDs remains unclear. Here, we discuss the current understanding on the roles of self-DNA and the cGAS/STING pathway in the pathophysiology of CVDs and the therapeutic potential of targeting this pathway.
Authors
Wataru Saitoh, Yasutomi Higashikuni, Oyunbileg Bavuu, Masataka Sata, Daiju Fukuda
Abstract
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed as a uniformly beneficial antiviral and antitumor signaling axis, emerging evidence reveals that cGAS-STING functions as a context-dependent immune rheostat whose impact is dictated by signal magnitude, timing, cellular origin, subcellular localization of signaling components, and tissue context. These parameters explain why pathway activation can promote tumor rejection, vaccine efficacy, and host defense in some settings yet drive immune suppression, metastasis, neuroinflammation, or autoinflammatory disease in others. In this Review, we synthesize mechanistic and clinical insights across agonist and antagonist strategies targeting the cGAS-STING pathway in cancer, infectious disease, neurodegeneration, and interferonopathies. We highlight why first-generation STING agonists have underperformed clinically and how next-generation delivery systems and cGAS-directed approaches may overcome these limitations. We propose a disease-centric framework that integrates spatial delivery, dosing architecture, and pharmacodynamic biomarker discovery to enable rational modulation of cGAS-STING, repositioning the pathway as a tunable immunologic control node for precision therapy rather than a binary on/off switch.
Authors
Akanksha S. Mahajan, Connor M. Forsyth, Cao Dai Phung, Xinhe Shen, Rachel Jarvis, Alexander H. Stegh
Abstract
The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriate or sustained activation of this pathway can drive chronic inflammation, autoimmunity, and disease-associated immune dysfunction, which can promote cancer growth. Effective immunity therefore depends on precise regulatory control that restrains cGAS/STING activity under homeostatic conditions while preserving the capacity for swift and robust responses to diverse danger signals. In this Review, we synthesize emerging principles that regulate cGAS/STING signaling across cellular contexts to control signal initiation, amplification, and termination. We discuss how disruption, persistence, or pathological rewiring of these regulatory processes contributes to immune imbalance across health and disease, promoting chronic inflammation, immunosuppression, and tissue pathology, with particular relevance to tumor progression and therapeutic resistance. Finally, we consider how restoring appropriate cGAS/STING regulation, rather than simply enhancing or inhibiting pathway activity, may reestablish immune homeostasis and improve therapeutic outcomes in cancer and other inflammatory diseases, framing the pathway as a dynamic regulatory circuit rather than a simple linear signaling cascade.
Authors
Min-Guk Cho, Rachel Lee, Jaycee Johnson, Gaorav P. Gupta
Abstract
As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.
Authors
Cornelia M. Weyand, Jörg J. Goronzy
Abstract
The reality of an aging population demands a deeper understanding of aging as a biological process, rather than as a chronological descriptor. Chronological age poorly captures interindividual heterogeneity in physiological and functional decline, disease susceptibility, and mortality risk. In contrast, biological age encompasses deterioration at the molecular, cellular, tissue, organ, functional, and organismal levels and provides insight into why two individuals with the same chronological age exhibit differences in physiological function, disease susceptibility, and mortality risk. While early models of biological age relied on functional markers or composite scores derived largely from longitudinal cohort studies, more recent models integrate molecular profiling with machine learning to ascertain biological aging trajectories. In parallel, new artificial intelligence tools have been applied to various imaging modalities and other forms of complex data to elucidate latent patterns and estimate biological age. In this state-of-the-art Review, we explore historical and modern approaches to estimating biological age and highlight key conceptual, technical, and translational challenges that remain unresolved. As geroscience-guided interventions are incorporated into clinical evaluations, robust and accurate interpretable measures of biological aging are crucial to ascertain treatment effects in clinical trials.
Authors
Baljash S. Cheema, Bedirhan Boztepe, Moses O. Awofolaju, Mallory S. Hubbard, William B. Marcus, Frank J. Palella, Mohamed Abdel-Mohsen, David M. Liebovitz, Manjot K. Gill, R. James Cotton, John T. Wilkins, Douglas E. Vaughan
Abstract
Each year, sepsis claims more lives in the United States than many major cancers and HIV/AIDS combined, yet therapeutic progress has been modest. Adding to this crisis is the alarming rise of multidrug-resistant “superbugs,” which increasingly render conventional antibiotics ineffective. Pathogen-targeted antibiotics will always remain a cornerstone of sepsis treatment, and research into novel antibiotics must continue unabated. However, the consistent mortality in sepsis tells us this approach is insufficient. Most deaths in sepsis do not occur during the early cytokine storm–driven hyper-inflammatory phase but rather days or weeks after the initial insult, during a protracted phase of immune suppression. Here, we make the case that a crucial way to reduce sepsis mortality lies in restoration of the patient’s immune competence, enabling the patient to contain and kill the invading microbes. Adjuvant immune therapies will not only enable killing of the initial, invading pathogens but also prevent secondary, hospital-acquired infections. Immunotherapy revolutionized oncology by challenging the assumption that cancer was best treated through cytotoxic or targeted tumor-directed approaches, and sepsis now stands at a similar inflection point. We argue that embracing immune restoration as a core therapeutic objective offers the most promising means to improve survival in this lethal disorder.
Authors
Richard S. Hotchkiss, Guillaume Monneret
Abstract
Polycystic ovary syndrome (PCOS), also known as polyendocrine metabolic ovarian syndrome (PMOS), is the most common endocrinologic disorder to affect women. Despite this, the pathophysiology of the disease is not entirely known. This has hindered the diagnosis of the disease and appropriate treatment for millions of individuals. In this Review, we discuss the proposed pathophysiology of PCOS from a translational perspective. We review the existing diagnostic criteria of PCOS and current management strategies. Finally, we discuss the long-term health sequelae associated with PCOS, future directions, and areas of needed research in this often-overlooked disease.
Authors
Jessica L. Chan, Irene Masini, Margareta D. Pisarska
Abstract
Breakthroughs in rare genetic disease research elucidate the relationships among cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes. Cytosolic self-DNA is a potent trigger of innate immunity, activating the DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). This pathway is negatively regulated by the DNA-degrading enzyme three-prime repair exonuclease 1 (TREX1); loss-of-function TREX1 variants lead to accumulation of cytosolic DNA, resulting in STING-mediated autoinflammation. Similarly, STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy, another disease characterized by multi-organ damage, disability, and premature death. The TREX1-cGAS-STING pathway has also been implicated in regulation of genome stability. Indeed, DNA damage lies at the heart of a separate TREX1-mediated disease, known as retinal vasculopathy with cerebral leukoencephalopathy, where the aberrant nuclear activity of mislocalized TREX1 damages genomic DNA, resulting in multi-organ degeneration syndrome with features of autoimmunity. Thus, monogenic autoimmune diseases and DNA damage syndromes sometimes overlap clinically, and the study of these diseases has created pathways for developing first-in-class small molecule therapeutics.
Authors
Debby J. Park, Kate M. Jones, Jessica B. Anderson, Amanda V. Finck, Jonathan J. Miner
Abstract
Identification of the genetic mutations underlying the ultrarare monogenic conditions STING-associated vasculopathy with onset in infancy (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome revealed a role for the stimulator of interferon genes (STING) immune pathway in the pathogenesis of interstitial lung disease (ILD) in these conditions. STING-focused therapeutics could be a potential avenue for the treatment of SAVI and COPA syndrome in the future, yet the relevance of STING to more common types of ILD is not clear. Here, we provide an overview of SAVI and COPA syndrome, the nature of ILD in these conditions, and current evidence regarding STING activity in their pathogenesis. We discuss data from studies of a variety of other ILDs and model systems and explore the potential role for STING in more common forms of ILD.
Authors
Prasad Palani Velu, Gaofeng Zhu, Karen J. Mackenzie
Abstract
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA–induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation–associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.
Authors
Weixi Feng, Abulimiti Aikedan, Subhash C. Sinha, Li Gan
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ISSN: 0021-9738 (print), 1558-8238 (online)