T cells are the core of adaptive immunity, and T cell function is markedly impacted by the accumulation of DNA damage. Studies have demonstrated that the dynamic balance between DNA damage and repair not only regulates T cell activation, differentiation and homeostasis maintenance (77), but is also closely associated with autoimmune diseases and immune senescence (78-80). During aging, T cells develop genomic instability due to decreased DNA repair capacity, manifesting as reduced proliferative potential and weakened effector functions, ultimately leading to immune senescence (81,82).

In autoimmune conditions, activated T cells accumulate ROS-induced oxidative DNA damage, creating a vicious cycle that further exacerbates inflammatory responses. In autoimmune hepatitis, for instance, CD4⁺ T cells exhibit markedly elevated 8-oxoguanine levels, which are positively associated with hepatic inflammation severity (12). Notably, regulatory T cells (Tregs), critical for immune tolerance maintenance, also exhibit DNA repair capacity-dependent function. Defects in BER pathway components in Tregs impair Foxp3 stability, driving their conversion to pro-inflammatory T helper 17 (Th17) cells and thereby disrupting autoimmune homeostasis (83-85) (Fig. 3).

As pivotal cytotoxic effectors, CD8⁺ T cells require stringent genomic stability to maintain their proliferative capacity, survival and effector functions. In the inflammatory milieu of autoimmune diseases, CD8⁺ T cells are subjected to sustained oxidative and replicative stress, leading to the accumulation of DNA damage, including oxidized bases (such as 8-oxoguanine) and DSBs (81,86). This damage accrual is not merely a passive consequence but an active driver of dysfunction. Mechanistically, unrepaired DNA damage in CD8⁺ T cells can trigger cell-intrinsic signaling cascades that promote a state of functional exhaustion or impaired differentiation. The cytoplasmic accumulation of nuclear or mitochondrial DNA (mtDNA) fragments, resulting from defective repair or mitochondrial distress, activates the cGAS-STING pathway (23,87). While this pathway is crucial for antitumor and anti-viral immunity, its chronic activation in autoimmune contexts drives CD8⁺ T cells toward an exhausted phenotype, characterized by increased expression of inhibitory receptors (such as programmed death 1 and T cell immunoglobulin and mucin domain-containing protein 3), impaired cytokine production [including interferon (IFN)-γ and TNF-α production] and reduced cytotoxic potential (23,83,87). This exhaustion-like state compromises their ability to clear aberrant self-reactive cells or regulate immune responses, thereby contributing to disease persistence. Furthermore, DDR deficiencies can directly alter CD8⁺ T cell metabolism and epigenetic programming. For instance, persistent DSB signaling can rewire cellular metabolism toward a suppressive state and enforce epigenetic changes that stabilize the exhausted transcriptional program (88). In patients with SLE and RA, CD8⁺ T cells often exhibit features of senescence and exhaustion, which are associated with disease activity and may be rooted in unresolved genomic stress (81,89).

As important effector cells of innate immunity, the functional state of macrophages (for example, pro-inflammatory M1-type or anti-inflammatory M2-type polarization) is closely related to the dynamic balance of DNA damage and repair mechanisms. During chronic inflammation and aging, the sustained DDR induces macrophage conversion to a pro-inflammatory phenotype (M1), and promotes the formation of an inflammatory microenvironment through the secretion of pro-inflammatory factors such as IL-1β and TNF-α (Fig. 3) (90). Genotoxic stresses in the microenvironment (including ROS, chemotherapeutic agents or radiation) can induce DNA damage in macrophages, which subsequently regulates their immune phenotype and function through activation of the cGAS-STING pathway or PARP-dependent repair pathways (91). Studies have demonstrated that mtDNA release drives M1 polarization of macrophages via the cGAS-STING pathway, while PARP-1 overactivation promotes inflammatory factor production by modulating NF-κB signaling (92,93). However, long-term DNA damage accumulation also leads to macrophage dysfunction, characterized by impaired phagocytic capacity and compromised antigen presentation, which contributes to tumor progression or senescence-associated inflammation (94,95) (Fig. 3). In the tumor microenvironment, macrophages frequently exhibiting DNA damage promote immune escape by secreting immunosuppressive factors such as IL-10 and TGF-β, whereas during aging, persistent DNA damage in macrophages alters their secretory phenotype, fostering chronic inflammatory conditions in tissues (Fig. 3). These findings reveal the central role of the DNA damage repair balance in regulating macrophage function, providing novel perspectives for the treatment of related diseases.

B cell activation and antibody production are strictly dependent on the maintenance of genomic stability (Fig. 3). The maintenance of B cell function depends on some specific DNA repair pathways, such as BER and HR. Impairment here markedly increases genomic instability in B cells, causing errors in somatic hypermutation and class switch recombination processes, ultimately resulting in aberrant antibody production or breakdown of immune tolerance (96). Toll-like receptor 9 (TLR9) recognizes pathogen DNA to drive B cell activation (97,98); however, the aberrant accumulation of self-nucleic acids due to nuclease deficiencies (for example, in TREX1) can be misrecognized by intracellular sensors such as TLR9 or cGAS-STING, driving inappropriate B cell activation and a type I interferon response that is central to the pathogenesis of systemic lupus erythematosus (99). In the tumor microenvironment, B cells mediate antitumor immunity via antigen presentation; however, their function is modulated by damage-associated molecular patterns (DAMPs) released from tumor cells. These DAMPs alter B-cell activation status, antigen presentation efficiency and costimulatory molecule expression (100). Notably, emerging evidence suggests that in pathological contexts such as chronic infection or cancer, persistent DNA damage stress within the tumor microenvironment can skew B cell differentiation. This may contribute to the expansion of regulatory B cells (Bregs) or otherwise dysfunctional B cells that promote immune escape by inducing immunosuppressive factor secretion (including IL-10 and TGF-β secretion) (101). A recent study has further revealed that specific DNA repair pathways, such as NHEJ, serve essential roles in B cell antibody diversity generation and affinity maturation (102). For example, during early development, NHEJ facilitates V(D)J recombination to assemble the primary B cell receptor repertoire; following activation, it ensures the fidelity of class-switch recombination to alter antibody class (102). This provides novel perspectives for understanding the central position of DNA repair mechanisms in adaptive immunity.

Innate immune cells [such as natural killer (NK) cells and dendritic cells] can sense DNA damage signals through nucleic acid sensors. For example, tumor-derived cfDNA or self-DNA released from cells can be taken up by antigen-presenting cells such as dendritic cells (DCs) (33). Activation of the cGAS-STING pathway in these DCs promotes their maturation and the production of cytokines (for example, type I interferons), which, in turn, can enhance NK cell activation and drive adaptive antitumor immunity (33,91,103,104). However, chronic DNA damage may lead to hyperactivation of intrinsic immunity, triggering autoinflammation or tissue damage (105). In addition, certain proteins involved in the DNA damage response exhibit immunomodulatory functions. For example, DNA repair factors (such as Growth arrest and DNA damage-inducible 45 family of proteins) have been shown to be involved in DNA repair and to regulate inflammatory responses in various cell types, playing an important immunoregulatory role in a variety of inflammatory and autoimmune diseases (106,107).

DNA damage drives inflammatory responses through multiple mechanisms. Acute damage (such as that caused by infection or radiotherapy) activates both the cGAS-STING and NF-κB pathways, promoting the release of pro-inflammatory factors such as IL-6 and TNF-α, thereby enhancing antitumor or antiviral immunity (94,103). Specifically, cGAS recognizes cytoplasmic DNA to form dimers that catalyze cyclic GMP-AMP production, subsequently activating the STING protein and initiating type I interferon responses (108). However, chronic damage (such as that caused by aging or metabolic stress) leads to a persistent inflammatory microenvironment that promotes tumor progression or aging-related diseases (90,109,110). For instance, senescent cells mainly create a persistent pro-inflammatory microenvironment via the senescence-associated secretory phenotype, which involves the secretion of a large number of chemokines (such as CCL2, CXCL1 and CXCL8). These factors actively recruit immune cells such as monocytes and neutrophils. These cells, together with the senescent cells themselves, release various inflammatory mediators, including IL-1, IL-6 and MMPs, thereby establishing a chronic low-grade inflammatory state (90,111). In addition, previous foundational studies, along with more recent work, have shown that DNA repair enzymes (such as mutT homologs) can maintain genomic stability by preventing the incorporation of oxidatively damaged nucleotides into DNA, offering a novel perspective for treating autoimmune diseases by targeting genomic instability (100,112).

DNA damage is a key driver of immune senescence, a process characterized by T cell dysfunction and chronic inflammation (81,113). Senescent T cells exhibit telomere shortening, mitochondrial dysfunction and sustained activation of the DDR signaling pathway (81,114). Specifically, telomeres are shortened by 50-100 base pairs annually on average, leading to upregulated expression of the cell cycle arrest-related protein p21. Concurrently, the mitochondrial membrane potential decreases, ATP production diminishes and mtDNA release occurs (114). Impaired DNA repair capacity, exemplified by excision repair cross-complementation group 1 (ERCC1) deficiency, accelerates hematopoietic senescence and compromises immune cell reconstitution (115,116). Hematopoietic stem cells with ERCC1 deficiency exhibit markedly reduced self-renewal capacity and a tendency to differentiate into myeloid cells rather than lymphoid cells, which disrupts immune homeostasis (116,117). Notably, an elevated frequency of mutations in DNA repair genes in the elderly population is associated with increased infiltration of CD8⁺ T cells and M1 macrophages, suggesting a complex association between the DDR and age-related immune remodeling (118). The frequency of somatic mutations in repair genes (such as TP53 and ATM) in peripheral blood cells of individuals >70 years of age is markedly higher than that of young adults (119,120). This genomic instability, combined with inflammatory immune cell infiltration, constitutes the molecular foundation of immune senescence. Interventional strategies, such as senolytics (senescent cell-targeting agents), delay immune senescence via senescent cell elimination or DNA repair enhancement ('genoprotection') (81,95,121). For instance, the combination of dasatinib and quercetin specifically clears senescent immune cells and restores thymic function (122).

In MS, a clinical study has confirmed significant oxidative DNA damage and impaired repair function in patients with MS (124). Research indicates increased DNA damage and delayed repair in peripheral blood lymphocytes of patients with MS, alongside downregulated expression of key BER enzymes (such as OGG1 and APE1). These molecular alterations in DNA integrity and repair capacity are implicated in the pathogenesis of MS and correlate with disease activity (Fig. 5) (124). Genetic polymorphisms further associate repair capacity with disease risk (124). This molecular damage has direct clinical relevance: The levels of oxidative DNA markers (such as 8-OHdG) in patient body fluids are positively associated with the severity of core symptoms, including neurological dysfunction, fatigue and cognitive impairment (Fig. 5) (167). Under chronic inflammatory conditions, persistent oxidative stress leads to the accumulation of 8-oxoguanine in DNA. During the attempt to repair this damage, the enzymatic activity of OGG1 itself triggers pro-inflammatory signaling pathways, thereby exacerbating the inflammatory response. OGG1 is a key enzyme for repairing oxidative DNA damage (particularly 8-oxoguanine). An animal study has demonstrated that inhibiting OGG1 activity can ameliorate symptoms of MS (Fig. 5) (85). Notably, epigenetic analyses have revealed abnormal hypermethylation in the promoter regions of specific BER genes within MS lesions, which may represent an important factor contributing to persistent repair dysfunction (168). In addition to nuclear DNA damage, oligodendrocytes in patients with active MS exhibit mitochondrial dysfunction, including markedly reduced membrane potential and ATP production (Fig. 4) (169). Research has demonstrated that the anti-inflammatory effects of small-molecule inhibitors in MS models, coupled with the effective promotion of remyelination by the epigenetic silencing inhibitor ESI1 in animal models of demyelination, together provide a preclinical theoretical foundation for intervening in MS by modulating DNA repair processes (85,168).

The pathogenesis of AIT is closely related to oxidative damage in thyroid follicular cells. Thyroid peroxidase (TPO) generates ROS during hormone synthesis, and its dysfunction can exacerbate the oxidative stress state (Fig. 5) (170,171). Excessive ROS can induce oxidative DNA damage, including 8-OHdG. A study has shown that in the thyroid tissue of patients with AIT and in experimental models, the levels of such DNA damage markers are markedly elevated, accompanied by inhibited DNA repair capacity (172). Persistent DNA damage can promote apoptosis of follicular cells, leading to the release of self-antigens such as TPO and thyroglobulin within the cells, thereby disrupting immune tolerance (Fig. 4) (171,172). Additionally, in patients with AIT, autophagosome formation-related genes, such as autophagy-related 101 and beclin 1, have been found to be hypomethylated, and this is associated with environmental iodine levels (173). In thyroiditis animal models, intervening in specific DNA repair mechanisms has been shown to alleviate thyroiditis (172). For example, overexpression of the DNA repair protein mutT homolog 1 (MTH1) can reduce inflammation and damage induced by high iodine levels. High iodine can induce DNA damage and inflammation in thyroid cells by inhibiting MTH1, and increasing the infiltration of Th17 cells in the thyroid (Fig. 5) (172).

The DDR in cancer therapy is a double-edged sword, as it is associated with both therapeutic efficacy and the risk of autoimmunity. Chemotherapy-induced DNA damage and tumor cell death can lead to the release of self-antigens and cytoplasmic nucleic acids (such as cytosolic chromatin fragments), which in turn activate innate immune pathways such as the cGAS-STING pathway (174,175). While this drives antitumor immunity, it also provides a theoretical basis for breaking self-tolerance and triggering treatment-related autoimmune phenomena (176,177). In addition, intrinsic defects in DDR genes (such as BRCA1/2 mutations) in tumor cells exacerbate genomic instability and increase tumor immunogenicity (178). While this may enhance the efficacy of immune checkpoint inhibitors, it could also elevate the risk of autoimmune reactions due to aberrant immune activation (178). Therefore, imbalance of the DDR constitutes a key hub linking the therapeutic effects of cancer treatment to autoimmune side effects. A recent study has suggested that precise regulation of the DDR through strategies may enhance antitumor immunity while reducing toxicity to normal lymphocytes, offering a novel direction for optimizing treatment strategies (179).

Inhibitors of ATM/ATR kinase, a central regulator of the DDR, enhance sensitivity to radiotherapy or chemotherapy by blocking cell cycle checkpoints (196,197) (Table II). Emerging studies have found that ATM/ATR inhibitors also promote remodeling of the tumor immune microenvironment through activation of the cGAS-STING pathway (198-200). For example, inhibition of ATR leads to accumulation of unrepaired cytoplasmic DNA, activates cGAS-STING pathway and induces type I interferon secretion, which enhances T cell infiltration and antitumor immunity (200,201). Emerging evidence from preclinical models supports the combination of ATM/ATR inhibitors and immune checkpoint inhibitors (for example, anti-PD-L1) as a promising strategy for synergistic antitumor activity (202,203); however, this strategy necessitates a balance between immune activation and carcinogenic risks arising from unresolved DNA damage accumulation (204).

Damage fragments (such as oxidized base modifications or DSB markers) in cfDNA can be used as biomarkers for real-time monitoring of the DNA repair status (210). For example, persistent high levels of the DNA damage marker γH2AX were detected after radiotherapy suggest insufficient DNA damage repair and may guide the timing of combination therapy with ATM/ATR inhibitor (197,202). In addition, tumor-specific cfDNA mutation profiles (for example, BRCA1/2 deletion) can predict PARP inhibitor efficacy, and immunotherapy responders often exhibit upregulated expression levels of STING pathway-related genes in cfDNA (26,202). Future development of highly sensitive assays and integrated multi-omics modeling is required to improve predictive accuracy.

DNA repair inhibitors face several challenges. PARP or ATM/ATR inhibitors may increase genomic instability in normal tissues due to off-target effects, with long-term PARP inhibitor use potentially inducing hematopoietic malignancies and ATR inhibitors exhibiting hepatotoxicity in mouse models (196,204,211,212). Furthermore, inhibition of specific repair pathways may force cells to rely on error-prone alternative mechanisms (such as microhomology-mediated end-joining), increasing oncogenic mutation risks (213). Significant differences exist in DNA repair capacity and dependency across tissues: Hematopoietic stem cells highly depend on NHEJ, whereas intestinal epithelial cells preferentially use HR (214), leading to notable efficacy and toxicity variations of the same inhibitor in different organs. Strategies addressing these limitations include developing tissue-selective delivery systems and intermittent dosing regimens (194,215). Future research should integrate single-cell sequencing with organoid models to elucidate tissue-specific DNA repair dynamic networks across spatiotemporal dimensions, thereby designing adaptive therapeutic strategies that can adjust according to repair status or cell cycle.

Notwithstanding the substantial advances in delineating the DDR-immune axis, critical gaps remain in mechanistic clarity and translational validation. First, the causal temporality between DDR defects and immune activation is still unclear. A study has shown that loss-of-function mutations of TREX1, an endoplasmic reticulum-associated exonuclease, can trigger uncontrolled cGAS-STING activation, which is associated with autoinflammatory diseases, including SLE (216). However, loss-of-function mutations in TREX1 are clearly pathogenic in monogenic diseases such as Aicardi-Goutières Syndrome, but their contribution to complex autoimmune diseases such as SLE still requires more population genetic studies. Second, the role of the cGAS-STING pathway in autoimmunity is contradictory and appears to be dual (152). On one hand, overactivation of this pathway is closely related to type I interferon-driven autoimmunity. On the other hand, animal models suggest that a simple genetic defect (such as TREX1 deficiency) may be insufficient to induce full tissue inflammation, often requiring an environmental 'second hit', indicating that its pathogenicity may be conditional rather than absolutely causative (217). Third, there is currently a lack of clinically validated, standardized DDR-derived biomarkers that can be used for disease stratification or efficacy prediction. Although DDR-related autoantibodies (such as anti-PARP zinc finger domain antibodies) are common in SLE and SS (39,218), biomarkers such as specific damage features of cfDNA, including oxidative modifications, have not yet been prospectively validated as reliable predictive tools, partly due to the lack of standardized detection methods.

A prioritized research agenda should address these gaps. Preclinically, using conditional knockout models of specific cells such as synovial cells, the cell-specific role of TREX1-cGAS crosstalk in RA and other diseases was precisely validated (219). In human cohorts, research suggests that specific forms of cfDNA, such as oxidatively modified DNA, may be associated with disease activity (220), providing a basis for its use as a biomarker for monitoring disease activity. A preclinical study suggests that PARP inhibitors may exert therapeutic effects through anti-inflammatory mechanisms, but their inhibitory effects on DNA repair could pose long-term genomic risks (221). Therefore, exploring dosing regimens that can distinguish between their anti-inflammatory effects and genotoxic effects (such as low-dose or intermittent administration) is a key direction for future research.