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DNA damage and repair mechanisms are crucial for maintaining genomic stability, and their dysregulation is closely linked to the complex pathogenesis of autoimmune diseases. The present review systematically describes the types of DNA damage, key repair pathways, their regulatory networks, and the multidimensional interactions between DNA repair and the immune system. Furthermore, it delves into how defective DNA repair drives the development of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis through mechanisms encompassing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway activation, self-antigen release and breakdown of immune tolerance. Oxidative stress-induced DNA damage, mutations in repair genes and aberrant accumulation of cytosolic DNA are key triggers of autoimmune responses. In addition, DNA repair proteins indirectly influence disease progression by modulating immune cell functions, including T-cell homeostasis and macrophage polarization. The present review further summarizes the therapeutic potential and challenges of targeting DNA damage response pathways, including via poly adenosine diphosphate ribose polymerase inhibitors and cGAS-STING axis regulation, as demonstrated in pre-clinical models. Future research leveraging multi-omics and innovative delivery systems will be crucial for translating these discoveries into effective, personalized therapies. The present review advances the development of personalized precision medicine and provides a solid theoretical foundation for developing novel treatment strategies.

The efficacy of immunotherapy in colorectal cancer (CRC) is frequently limited by an immunosuppressive tumor microenvironment. Here, we identify exonuclease/endonuclease/phosphatase domain‐containing protein 1 (EEPD1), a gatekeeper of homologous recombination (HR) repair, as a key driver of this immune exclusion. Downregulation of EEPD1 profoundly compromises HR in CRC cells, which curtails their proliferative and metastatic capacities in vitro and in vivo. Mechanistically, EEPD1 deficiency fuels genomic instability, leading to cytosolic DNA accumulation and activation of the cGAS‐STING‐type I interferon axis. This cascade promotes dendritic cell maturation, skews macrophages toward a proinflammatory M1 phenotype, and enhances tumor‐associated antigen presentation, culminating in robust CD8+ T cell activation and cytotoxicity. Our findings elucidate a direct mechanism by which targeting EEPD1 sensitizes CRC to anti‐PD1 immunotherapy. Our work establishes EEPD1 as a promising therapeutic target to overcome immune checkpoint blockade resistance in colorectal cancer. In colorectal cancer, high expression of the DNA repair protein EEPD1 correlates with immune exclusion and poor prognosis. This study demonstrates that EEPD1 depletion induces genomic instability, leading to cytosolic DNA accumulation and subsequent activation of the cGAS‐STING‐type I interferon pathway. This cascade remodels the tumor microenvironment by promoting dendritic cell maturation, M1 macrophage polarization, and CD8+ T cell‐mediated cytotoxicity, ultimately sensitizing tumors to anti‐PD1 immunotherapy and establishing EEPD1 as a promising therapeutic target.

The cGAS‐STING pathway, a critical cytosolic DNA‐sensing mechanism in innate immunity, holds significant promise for cancer immunotherapy. However, conventional DNA‐damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING‐mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress‐induced nanoreactor composed of a pH‐responsive zeolitic imidazolate framework‐8 encapsulating telomerase‐targeted 6‐thio‐2’‐deoxyguanosine (6‐thio‐dG), with TIM‐3 antibodies (αTIM‐3) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6‐thio‐dG to induce tumor cell‐specific telomeric DNA damage. Concurrently, the αTIM‐3 blocks TIM‐3 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual‐action strategy drives robust cGAS‐STING activation, enhancing type I interferon production and DCs maturation. In murine models of immunogenic and poorly immunogenic tumors, the nanoreactor significantly suppresses tumor growth and prolongs survival. By coupling tumor‐intrinsic telomere stress with DC‐extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS‐STING pathway activation, presenting a promising therapeutic strategy for telomerase‐positive malignancies. A programmable nanoreactor was engineered for precise cGAS‐STING pathway activation in cancer immunotherapy. This strategy bridges targeted tumor DNA damage with DC immunomodulation, providing a translatable platform to unlock innate and adaptive antitumor immunity.

The cGAS‐STING pathway is emerging as an essential driver in systemic lupus erythematosus (SLE). Here, we characterize the key signature of cGAS‐STING pathway and its roles in SLE by leveraging large‐scale transcriptomics, cell‐based assays, and two lupus‐like mouse models. We identify a STING‐dependent gene signature termed M7core, enabling quantitative assessment of cGAS‐STING pathway activity in SLE. M7core reveals widespread cGAS‐STING pathway activation in 70.4% of 3,180 SLE samples and predicts therapeutic response to STING antagonists in 74.1% of patients, with higher activity indicating greater sensitivity. Across ten independent cohorts, M7core outperforms interferon‐stimulated gene signatures (mean AUROC = 0.876) and correlates with disease activity, anti‐dsDNA antibodies, lymphopenia, and lupus nephritis. Hydroxychloroquine treatment reduces M7core expression and its clinical associations. Importantly, in cGAS‐STING pathway‐driven lupus‐like mice, STING antagonist administration ameliorates multiorgan pathology and suppresses M7core genes participating in promoting inflammation, type I interferon, and cell death, including ZBP1—an established cGAS‐STING pathway facilitator. Notably, ZBP1 deficiency phenocopies blocking cGAS‐STING pathway‐mediated autoimmune pathology exacerbation in pristane‐induced lupus‐like mice, underscoring its context‐dependent roles in lupus pathogenesis. Together, these findings define M7core as a robust diagnostic and mechanistic biomarker and highlight the necessity of assessing pathway activity before initiating STING‐targeted therapy in SLE. Zhang et al. identify M7core, a critical cGAS‐STING pathway‐driven gene signature that is activated in most lupus patients’ blood and links to lupus disease severity, lymphopenia, and lupus nephritis. They further reveal the diagnostic and pathogenic characteristics of M7core and emphasize the importance of assessing pathway activity before initiating STING antagonist therapy in lupus.

Although nanozymes are potential tumor therapeutics due to their ability to disrupt intracellular redox homeostasis, developing nanozymes with higher therapeutic efficacy and clarifying their antitumor mechanism are challenging. Here, an iridium (Ir)‐based nanozyme (IIN) was constructed through coordination‐driven co‐assembly using photosensitizer indocyanine green (ICG), Ir, and indoleamine 2,3‐dioxygenase (IDO) inhibitor NLG8189. Then, the IIN was mimicked by tumor cell lysate (TCL)‐simulated dendritic cell (DC) membrane to form IIN@M. Based on superior enzyme‐like activity and photothermal performance, IIN@M disrupted the intracellular redox homeostasis by generating reactive oxygen species (ROS) and depleting glutathione (GSH). GSH depletion induced ferroptosis, and ROS burst under photothermal irradiation triggered pyroptosis, thus synergistically enhancing immunogenic cell death (ICD). The generated ROS could promote mitochondrial DNA (mtDNA) oxidative damage and release, finally activating the immune response by the cyclic GMP‐AMP synthase‐simulator of interferon gene (cGAS‐STING) pathway. In vivo experiments also suggested that IIN@M could efficiently ablate the primary tumor, especially under photothermal irradiation. Furthermore, it could suppress distant tumor progression by triggering the immune response, especially under photothermal irradiation, which was accompanied by increased DC maturation, M1 macrophage polarization, and T cell infiltration in tumor tissue. This study proposed a promising strategy for effective Ir‐based nanozyme in tumor immunotherapy. This study develops an iridium‐based nanozyme (IIN@M) with superior enzyme‐like activity and photothermal performance. It disrupts intracellular redox balance by generating reactive oxygen species and depleting glutathione, which synergistically induces ferroptosis, pyroptosis, and immunogenic cell death. Meanwhile, it activates the Stimulator of Interferon Genes pathway to initiate immune responses. Therefore, it effectively ablates primary tumors and inhibits distant tumor growth.

Background Esophageal squamous cell cancer (ESCC) is a malignancy derived from the Esophagus, and dysregulation of the cGAS‐STING pathway contributes to ESCC progression. Method ESCC bulk‐seq dataset GSE38129 was acquired from GEO database and then underwent Limma and WGCNA analysis for the identification of shared DEGs, which were intersected with cGAS‐STING pathway gene list and underwent Cox regression analysis for recognized cGAS‐STING associated prognostic indicators. Next, Consensus clustering and machine learning combinations (Lasso + SurvivalSVM) were utilized for cGAS‐STING associated ESCC molecular subgroups and prognostic model construction in TCGA‐ESCC cohorts, and prognostic performance was validated in GSE53662. Besides, hub prognostic variables were acquired from Lasso‐Cox regression, and their molecular and immune features were estimated via multiple bioinformatic approaches at TCGA‐ESCC cohort. In addition, heterogeneity of hub genes at single‐cell level for ESCC patients was also indicated in GSE188900 in spatial and temporal manners. Furthermore, Drug sensitivity and molecular docking analysis were performed for identification of optimal therapeutic agents targeting hub genes. Indeed, in vitro assays have been performed to assess the oncogenic potential of hub genes and efficacy of optimal therapeutic agents. Furthermore, implications of hub genes with cGAS‐STING pathway were estimated in single‐cell artificial intelligence (AI) driven‐virtual cell and bulk assays. Results By utilizing integrative AI and multi‐omic pipelines, we proved that the cGAS‐STING pathway can guide subgroup stratification and prognostic model construction for ESCC patients. PRKDC and SLC25A13 can be considered hub genes associated with ESCC pathogenesis and regulation of the cGAS‐STING pathway. BX‐912 and Navitoclax can be considered drug screening strategies for the treatment of ESCC patients by targeting PRKDC and SLC25A13. Conclusion cGAS‐STING pathway can guide risk stratification and can be considered as a therapeutic target for ESCC patients, which provides novel insights into precision and personalized medicine for ESCC patients.

Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS‐STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS‐ALS. Therefore, we analyzed innate immune pathways in FUS‐ALS, which revealed upregulation of interferon‐stimulated genes (ISGs) and activation of the TBK1‐IRF3 pathway in FUSmut iPSC‐derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG‐I, but not MDA5, was found to be significantly upregulated in FUSmut sMNs, which was abolished upon siRNA‐mediated knockdown of RIG‐I. RIG‐I was highly expressed in FUS‐ALS post‐mortem α‐MNs. IFN treatment of FUSwt sMNs phenocopied the axonal degeneration of FUSmut sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS‐ALS sMNs. The JAK‐STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS‐ALS patients, eight of whom had a significantly elevated interferon signature. RIG‐I‐mediated innate immune activation in sMNs may be an interesting novel individualized biomarker‐driven therapeutic target in (FUS‐) ALS. A one‐sentence summary of your paper: RIG‐I‐mediated innate immune activation is found in FUS‐ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK‐STAT inhibition and might thus be an interesting novel individualized biomarker‐driven therapeutic approach in (FUS‐) ALS. Using iPSC‐derived motoneurons and postmortem tissue from FUS‐ALS patients, it is demonstrated that increased mitochondrial transcription leads to elevated cytosolic double‐stranded RNA (dsRNA) levels. This aberrant accumulation activates a RIG‐I–dependent innate immune response leading to neurodegeneration, which is amenable for FDA‐ and EMA‐approved JAK inhibitors providing an interesting novel individualized biomarker‐driven therapeutic approach for (FUS‐) ALS.

Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting in high recurrence rates in patients. Herein, a bioactive injectable hydrogel (BG‐Mngel) formed by crosslinking sodium alginate (SA) with manganese‐doped bioactive glass (BG‐Mn) is developed as a versatile platform for anti‐tumor immunotherapy and postoperative wound healing for melanoma. The incorporation of Mn2+ within bioactive glass (BG) can activate the cGAS‐STING immune pathway to elicit robust immune response for cancer immunotherapy. Furthermore, doping Mn2+ in BG endows system with excellent photothermal properties, hence facilitating STING activation and reversing the tumor immune‐suppressive microenvironment. BG exhibits favorable angiogenic capacity and tissue regenerative potential, and Mn2+ promotes cell migration in vitro. When combining BG‐Mngel with anti‐PD‐1 antibody (α‐PD‐1) for the treatment of malignant melanoma, it shows enhanced anti‐tumor immune response and long‐term immune memory response. Remarkably, BG‐Mngel can upregulate the expression of genes related to blood vessel formation and promote skin tissue regeneration when treating full‐thickness wounds. Overall, BG‐MnGel serves as an effective adjuvant therapy to regulate tumor metastasis and wound healing for malignant melanoma. A bioactive injectable hydrogel (BG‐MnGel) is developed for anti‐tumor immunotherapy and wound healing of melanoma. Incorporation of Mn2+ in BG endows system with excellent photothermal properties, hence facilitating stimulator of interferon genes (STING) activation and reversing the tumor immune‐suppressive microenvironment. Furthermore, BG exhibits favorable angiogenic capacity and tissue regenerative potential, making it promising for the treatment of malignant melanoma.

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.

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.