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Cellular senescence is historically regarded as a tumor suppression mechanism to prevent damaged cells from aberrant proliferation in benign and premalignant tumors. However, recent findings have suggested that senescent cells contribute to tumorigenesis and age‐associated pathologies through the senescence‐associated secretory phenotype (SASP). Therefore, to control age‐associated cancer, it is important to understand the molecular mechanisms of the SASP in the cancer microenvironment. New findings have suggested that the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling pathway, a critical indicator of innate immune response, triggers the SASP in response to accumulation of cytoplasmic DNA (cytoplasmic chromatin fragments, mtDNA and cDNA) in senescent cells. Notably, the cGAS‐STING signaling pathway promotes or inhibits tumorigenesis depending on the biological context in vivo, indicating that it may be a potential therapeutic target for cancer. Herein, we review the regulatory machinery and biological function of the SASP via the cGAS‐STING signaling pathway in cancer. This brief review discusses the role of the senescence‐associated secretory phenotype (SASP) and cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) signaling pathway on cellular senescence in cancer development. We suggest that the cGAS‐STING signaling pathway may be a novel target for induction of SASP.

Ataxia‐telangiectasia (A‐T) is a genetic disorder caused by the lack of functional ATM kinase. A‐T is characterized by chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A‐T remains elusive. Here, we utilize human pluripotent stem cell‐derived cortical brain organoids to study A‐T neuropathology. Mechanistically, we show that the cGAS‐STING pathway is required for the recognition of micronuclei and induction of a senescence‐associated secretory phenotype (SASP) in A‐T olfactory neurosphere‐derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self‐DNA‐triggered SASP expression in A‐T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A‐T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A‐T and constitutes a novel therapeutic target for treating neuropathology in A‐T patients. Aguado et al. show that senescent astrocytes upregulate detrimental pro‐inflammatory SASP factors in a cGAS/STING‐dependant manner that promote accelerated ageing in brain organoids of ataxia‐telangiectasia. Pharmacological interventions in these organoids with cGAS and STING inhibitors reduce astrocyte senescence and the SASP, and consequently, improve neuronal activity and survival.

Immune checkpoint blockade (ICB) has significantly advanced cancer immunotherapy, yet its patient response rates are generally low. Vaccines, including immunostimulant‐adjuvanted peptide antigens, can improve ICB. The emerging neoantigens generated by cancer somatic mutations elicit cancer‐specific immunity for personalized immunotherapy; the novel cyclic dinucleotide (CDN) adjuvants activate stimulator of interferon genes (STING) for antitumor type I interferon (IFN‐I) responses. However, CDN/neoantigen vaccine development has been limited by the poor antigen/adjuvant codelivery. Here, pH‐responsive CDN/neoantigen codelivering nanovaccines (NVs) for ICB combination tumor immunotherapy are reported. pH‐responsive polymers are synthesized to be self‐assembled into multivesicular nanoparticles (NPs) at physiological pH and disassembled at acidic conditions. NPs with high CDN/antigen coloading are selected as NVs for CDN/antigen codelivery to antigen presenting cells (APCs) in immunomodulatory lymph nodes (LNs). In the acidic endosome of APCs, pH‐responsive NVs facilitate the vaccine release and escape into cytosol, where CDNs activate STING for IFN‐I responses and antigens are presented by major histocompatibility complex (MHC) for T‐cell priming. In mice, NVs elicit potent antigen‐specific CD8+ T‐cell responses with immune memory, and reduce multifaceted tumor immunosuppression. In syngeneic murine tumors, NVs show robust ICB combination therapeutic efficacy. Overall, these CDN/neoantigen‐codelivering NVs hold the potential for ICB combination tumor immunotherapy. Cancer neoantigens and cyclic dinucleotide (CDN) vaccines can improve immune checkpoint blockade (ICB) immunotherapy, but have poor codelivery. Here, pH‐responsive nanovaccines are reported that efficiently codeliver CDNs/antigens to the cytosol of lymph nodal antigen presenting cells, resulting in efficient STING activation, durable antigen presentation, potent CD8+ T‐cell responses with memory, reduced tumor immunosuppression, and robust ICB combination tumor therapy.

Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease in the tropics and subtropics with high morbidity and mortality. The facultative intracellular bacterium induces host cell fusion through its type VI secretion system 5 (T6SS5) as an important part of its pathogenesis in mammalian hosts. This allows it to spread intercellularly without encountering extracellular host defenses. We report that bacterial T6SS5-dependent cell fusion triggers type I IFN gene expression in the host and leads to activation of the cGAMP synthase–stimulator of IFN genes (cGAS–STING) pathway, independent of bacterial ligands. Aberrant and abortive mitotic events result in the formation of micronuclei colocalizing with cGAS, which is activated by double-stranded DNA. Surprisingly, cGAS–STING activation leads to type I IFN transcription but not its production. Instead, the activation of cGAS and STING results in autophagic cell death. We also observed type I IFN gene expression, micronuclei formation, and death of chemically induced cell fusions. Therefore, we propose that the cGAS–STING pathway senses unnatural cell fusion through micronuclei formation as a danger signal, and consequently limits aberrant cell division and potential cellular transformation through autophagic death induction.

ABSTRACT Senescent cells are known to contribute to aging and age‐related diseases. One key way they influence aging is by secreting senescence‐associated secretory phenotype (SASP) factors along with several damage‐associated molecular pattern (DAMP) molecules. Consequently, inhibiting SASP and DAMP signaling (senomorphics) has emerged as a therapeutic strategy. Urolithin A (UA), a gut‐derived metabolite produced from ellagitannins and ellagic acid found in berries, nuts, and pomegranates, has demonstrated potent anti‐inflammatory properties and protective effects against aging and age‐related conditions in experimental models. Here we demonstrate that UA lowers the expression and release of pro‐inflammatory SASP and DAMP factors, at least in part, by downregulating cytosolic DNA release and subsequent decrease in cGAS‐STING signaling. Senescent cells accumulate extranuclear DNA fragments that are recognized by the cyclic GMP‐AMP synthase (cGAS) and its effector protein stimulator of interferon genes (STING), which promotes expression of SASP and DAMP genes by inducing nuclear factor‐kappa B (NF‐κB) and IFN regulatory factor 3 (IRF3) translocation. UA inhibits this process by preventing cytosolic DNA leakage and reducing cGAS‐STING signaling.

Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one‐year‐old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double‐stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS‐STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS‐STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS‐STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity. The high level of uterine E2 impairs uterine receptivity in aged mice. The increase of PRELAMIN A, PROGERIN and cytoplasmic DNA in aged mouse uterus leads to activation of cGAS‐STING pathway. CD14 accumulation derived from activated cGAS‐STING causes abnormal receptivity.

Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored.

The cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway has been a promising target for anticancer immunity, but rationally activating and enhancing this pathway in tumour cells is critical. Herein, a glutathione sensitive ZnFe2O4‐based nanosystem is developed to programmatically initiate and enhance the STING signalling pathway in tumour cells. The prepared ZnFe2O4 nanoparticles were coated with cancer cell membrane (CCM), which enabled the nanosystem target tumour cells. In tumour cells, ZnFe2O4 nanoparticles could be disintegrated by responding to high level glutathione, and the released Fe3+ generated reactive oxygen species to induce the DNA leakage into the cytoplasm to stimulate cGAS. Then Zn2+ promoted cGAS‐DNA phase separation to intensify the cGAS enzymatic activity. In addition, the low dose encapsulation of paclitaxel (PTX) acting as an antimitotic agent (ZnFe2O4‐PTX@CCM) ensured the sustained activation of cGAS/STING pathway. The in vitro and in vivo results confirmed that ZnFe2O4‐PTX@CCM elevated the cGAS/STING activity, promoted dendritic cell maturation, increased cytotoxic T lymphocyte and natural killer cells infiltration, eventually inhibiting the tumour progress and postoperative recurrence. This study provided feasible references on constructing STING activation nanosystem for tumour immunotherapy. Tailor‐designed ZnFe2O4‐based nanosystem can respond to the tumour microenvironment and stimulate anti‐tumour immune responses by enhancing the cGAS/STING pathway. Moreover, it remodels immunosuppressive microenvironment, and effectively inhibits tumour growth as well as postoperative recurrence.

The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.

ABSTRACT DNA‐dependent activator of interferon‐regulatory factors (DAI) has recently been identified to trigger ferroptosis in endothelial cells. However, it remains unclear whether it can also elicit ferroptosis in tumor cells and further remodel the tumor immune microenvironment (TIME). In this study, we found that activation of DAI could also trigger mouse colorectal cancer (CRC) cells ferroptosis. Further experiments showed that DAI‐driven ferroptosis induced mitochondria oxidative stress and dysfunction, leading to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway and thereby reprogrammed the TIME by promoting tumor‐associated macrophages (TAMs) M1 polarization while preventing TAMs from polarizing towards M2 type, exerting an effective anti‐tumor effect, which significantly reduced tumor size and weight. In summary, our findings confirmed DAI‐triggered ferroptosis‐induced mtDNA‐mediated cGAS‐STING anti‐tumor immunity pathway in mouse CRC cells, providing novel insights into the development of more effective tumor immunotherapeutic strategies that are based on DAI‐mediated programmed cell death (PCD). Our study identified and preliminarily elucidated the ferroptosis‐induced cGAS‐STING‐mediated anti‐tumor pathway triggered by DAI in colorectal cancer cells, providing new insight into the role of PCD in anti‐tumor immunotherapy and screening out potential targets for the treatment of colorectal cancer.