Review ArticleReview
Open Access

Treatment implications of T cell DNA damage in anti-tumor immunity

Xiaofei Jiao, Yiyang Shen, Yixuan Tang, Jiahao Liu and Qinglei Gao
Cancer Biology & Medicine May 2026, 20260020; DOI: https://doi.org/10.20892/j.issn.2095-3941.2026.0020

Abstract

T cell activity is fundamental to effective immunotherapies and sustained tumor control. Recent studies have demonstrated that the therapeutic potential of T cells is notably affected by DNA damage dynamics. Notably, DNA damage within T cells is both a predictive biomarker for therapeutic responses and a druggable vulnerability whose modulation enhances the anti-tumor efficacy of immunotherapies and targeted treatments. This review is aimed at assessing current understanding of the origins of DNA damage in T cells, its consequences, and therapeutic implications within the tumor microenvironment and during anticancer treatment. By elucidating the mechanisms through which DNA damage dictates T cell fate and function, we highlight its dual role as a biomarker and a therapeutic target. Our goal is to accelerate the optimization of immunotherapeutic regimens and the development of combinatorial approaches leveraging a dynamically regulated immune microenvironment by integrating T cell-intrinsic DNA damage response into patient stratification and trial design, together with rational optimization of genotoxic therapies and immunotherapy, to enable a durable response while minimizing immune toxicity.

keywords

Introduction

Tumors pose a major global health challenge, because of their high motility and associated morbidity1,2. Over the past few decades, anti-tumor therapies have undergone a paradigm shift from traditional chemotherapy to targeted therapies and, most notably, immunotherapies3–5. The efficacy of immunotherapies, particularly immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T cell therapy, is well established across various cancer types6–8. Additionally, the integration of chemotherapy and targeted agents with intrinsic immunomodulatory properties exhibits potent synergy with immunotherapy and consequently yields superior clinical outcomes9–11. The success of these strategies relies on enhancing T cell activity, which is fundamental to achieving durable tumor remission12. However, T cell function is complex and highly sensitive to both endogenous and exogenous factors, particularly disruption due to DNA damage13.

Within the tumor microenvironment (TME), DNA damage occurs in both cancerous and non-cancerous cells through various mechanisms, including rapid proliferation, replication stress, metabolic reprogramming, intercellular crosstalk, and therapeutic interventions14. Inducing DNA damage and hindering its repair in cancer cells is clinically beneficial, as evidenced by the application of chemotherapy and radiotherapy15. More recently, targeted therapies that directly inhibit DNA damage repair have emerged as important anti-tumor treatment targets. Inhibitors of poly (ADP-ribose) polymerase (PARP), ataxia telangiectasia and Rad3-related protein (ATR), ataxia-telangiectasia mutated kinase (ATM), checkpoint kinase 1 (CHK1), and WEE1 are currently under clinical development16. Among these, PARP inhibitors have the broadest clinical utility in treating ovarian, breast, and prostate cancers17,18.

A link has been established between DNA damage in cancer cells and enhanced antitumor immunity19. Cytosolic chromatin fragments produced by DNA damage activate the cGAS-STING pathway in cancer cells, thus promoting type I interferon production and facilitating T cell recruitment into tumor sites20–22. Additionally, Toll-like receptors and Z-DNA binding protein 1 (ZBP1) are cytosolic DNA sensors involved in the activation of intrinsic immune responses and the release of pro-inflammatory cytokines23,24. Consequently, T cell activity has emerged as a critical determinant of therapeutic outcomes in response to DNA-damaging agents, thus paving the way to combination strategies integrating DNA damage induction with immunotherapies, notably ICBs and CAR-T cells25,26.

Despite this progress, the field has largely treated T cells as passive responders to tumor-intrinsic DNA damage, and the effects of DNA damage within T cells themselves have received comparatively little attention. However, recent studies have indicated that T cell-intrinsic DNA damage and repair dynamics shape T cell survival, differentiation, and effector function, and therefore is a critical, yet previously overlooked, target for intervention27. Accordingly, this review outlines the sources of DNA damage in T cells, the downstream consequences for T cell fate and function, and the resulting treatment implications. By highlighting the need to safeguard T cell genomic integrity, we aim to help the field advance beyond a tumor-centric view of genotoxic therapy and position T cell DNA damage as an essential yet long underappreciated factor for optimizing therapeutic efficacy, minimizing immune attrition, and advancing rational combination regimens from bench to bedside.

Origins of T cell DNA damage in the TME

Increasing evidence indicates that DNA damage occurs in T cells during anti-tumor treatment under the stimulation of various endogenous and exogenous factors (Figure 1). Endogenous factors include the T cell activation process itself and germline mutations in DNA damage response (DDR) pathways. Meanwhile, exogenous inducers, such as metabolic competition within TME, genetic engineering processes for adaptive cell therapy, and the adverse effects of anti-tumor treatments, can also cause persistent DNA damage in T cells.

Figure 1
Figure 1

Factors affecting T cell DNA damage in the tumor microenvironment. This schematic illustrates the endogenous and exogenous factors that contribute to DNA damage in T cells. (A) Activation-induced T cell DNA damage: TCR activation augments mitochondrial ROS production, and CD38 overexpression depletes NAD+, thus impairing PARP-mediated DNA damage repair. (B) DNA damage repair-related germline mutations: Alterations in key DDR genes, such as ATM deficiency and BRCA1/2 mutations, compromise genomic stability and increase susceptibility to DNA damage. (C) Immunosuppressive TME-mediated DNA damage: Tumor cells can directly cause T cell DNA damage. Tregs induce hypoglycemia via glucose competition, whereas MDSCs generate NO, which in turn causes DNA deamination. (D) Anti-cancer treatment and genome editing: Therapeutic interventions such as radiotherapy, chemotherapy, DNA damage response inhibitors, and genome-editing approaches further modulate T cell genomic integrity. ATM, ataxia-telangiectasia mutated; BRCA1/2, breast cancer susceptibility gene 1/2; DDR, DNA damage response; GLUTs, glucose transporters; MDSCs, myeloid-derived suppressor cells; NAD+, nicotinamide adenine dinucleotide; NO, nitric oxide; PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species; TCR, T cell receptor; TME, tumor microenvironment; Tregs, regulatory T cells. Created with BioRender.com.

Notably, T cell DNA damage comprises multiple types under various genotoxic factors. In the reactive oxygen species (ROS)-enriched TME, oxidative base lesions and single-strand breaks are frequently observed28,29. In contrast, radiotherapy and chemotherapies can directly induce double-strand breaks (DSBs)30,31. Other factors, such as chronic antigen stimulation and rapid proliferation, instead impose replication stress. These lesions activate overlapping yet non-identical DDR signaling. Repair of oxidative and single-strand breaks relies on PARP-dependent signaling and the base excision repair pathways32,33. Replication-associated lesions (stalled or collapsed forks) preferentially engage the ATR-CHK1 axis, whereas DSBs primarily engage ATM and DNA-PK to initiate repair through NHEJ or HR34. Consequently, these differences can translate into divergent functional outcomes such as transient cell-cycle arrest followed by functional recovery, or sustained DDR that triggers senescence-like programs and apoptosis.

Endogenous factors

Activation state-dependent DNA damage and DDR in T cells

DNA damage signaling and repair in T cells are influenced by activation status. In resting T cells, upstream DDR kinases including ATM/ATR/DNA-PKcs are activated under genotoxic stress induced by zeocin, yet they do not efficiently assemble γH2AX and 53BP1 repair foci, thus leading to persistent unrepaired DNA lesions and heightened apoptosis. In contrast, activated T cells form abundant γH2AX/53BP1 foci and repair DNA damage more effectively, thereby exhibiting increased damage tolerance35.

Despite this enhanced tolerance, chronic activation also amplifies the burden of DNA lesions of T cells in the TME. Persistent antigen stimulation and T cell receptor (TCR) activation are key drivers in the TME that affect T cell expansion, differentiation, and function36. Antigen-activated lymphocytes undergo rapid cell division during immune responses, thereby leading to substantial genomic stress37. TCR activation via CD3/CD28 for 24 h has been found to trigger detectable DNA damage in T cells, as evidenced by markedly elevated expression of DNA damage markers, including phosphorylated ATM (pATM), PARP1, and mutS homolog 2 (MSH2)27. More importantly, various T cell subsets exhibit differential sensitivity to CD3/CD28 stimulation-induced DNA damage. As indicated by pATM levels, exhausted T cells (TEX) show the greatest increase, thus suggesting the highest susceptibility to DNA damage, and are followed by central memory T cells (TCM), stem cell-like memory T cells (TSCM), effector memory T cells (TEM), and terminally differentiated effector memory T cells (TEMRA). Elevated γH2AX and pATM have also been observed in human lymphocytes activated by phytohemagglutinin38.

The mechanisms underlying activation-induced DNA damage in T cells remain unclear. Current evidence supports a multifactorial model in which proliferative replication stress and activation-driven metabolic remodeling together increase the DNA damage burden. After T cell activation, rapid clonal expansion imposes replicative stress and consequently promotes formation of DNA lesions. In parallel, the enhanced metabolic activity, particularly increased mitochondrial function and subsequent increases in ROS post-T cell activation, might also be major sources of genotoxic stress39,40. Additionally, elevated NADPH oxidases and lipid metabolism might contribute to ROS accumulation during T cell activation41–43. Beyond damage induction, persistent antigen stimulation can also compromise DNA repair ability. In a chronic hepatitis B virus infection model, Montali et al.44 have reported that chronic T cell activation upregulates CD38, which functions as an NAD+ hydrolase. Hence, CD38 overexpression accelerates NAD+ depletion and impairs PARP-dependent repair, because NAD+ is a critical ADP-ribose donor for PARP-mediated poly(ADP-ribosyl)ation during the DDR. However, whether a similar regulatory pattern might operate within the TME remains to be fully elucidated and warrants further investigation. In addition, 2 major redox couples operate within cells: (1) the NADH/NAD+ redox pair, which primarily regulates mitochondrial bioenergetics and metabolic redox balance, and (2) the NADPH/NADP+ pair, which provides reducing equivalents to antioxidant defense systems, thereby sustaining cellular redox homeostasis. Therefore, CD38-driven perturbation of NAD+ homeostasis primarily disrupts metabolic redox balance, promotes ROS accumulation44, and exacerbates DNA damage in T cells. However, whether this CD38-NAD+ axis might operate similarly in tumor-infiltrating T cells, given the unique TME, remains to be validated in cancer-specific models. Notably, γH2AX upregulation is more pronounced in T cells derived from older rather than younger donors45.

DNA damage repair deficits due to germline mutations

Unrepaired DNA lesions can also accumulate because of deleterious germline mutations in DDR genes in T cells. Ataxia telangiectasia (A-T), an autosomal recessive disorder caused by pathogenic mutations in the ATM gene, is characterized by lymphopenia, genomic instability, and a predisposition to lymphoid malignancies. Compared with ATM wild-type (ATMwt/wt) T cells, ATM-deficient T cells exhibit proliferation defects and a higher percentage of γH2AX-positive S-phase cells, which are associated with elevated replication stress46–49. Importantly, these T cell-intrinsic ATM deficiencies can translate to clinically relevant limitations in adoptive immunotherapy. One study has generated CAR-T cells using primary T cells isolated from patients with A-T (ATM−/−) and healthy donors (ATMwt/wt). Strikingly, the ATM−/− CAR-T cells demonstrated elevated chromosomal abnormalities at CAR integration sites, concomitantly with functional impairment; these findings underscore the essential role of ATM in maintaining genomic stability during CAR-T cell manufacturing50.

Beyond ATM, germline defects in other DDR pathways, most notably BRCA 1/2, similarly perturb T cell development and homeostasis. Germline mutations in BRCA genes confer elevated lifetime risk of breast and ovarian cancers. BRCA1/2 genes are also crucial for maintaining genomic stability by facilitating DNA DSB repair through homologous recombination. In T cells, BRCA deficiency promotes thymocyte apoptosis and inhibits cell proliferation via upregulation of DNA damage and p53 activation51–53. In agreement with these findings, clinical data have further revealed that non-cancerous BRCA mutation carriers exhibit lower abundance of circulating CD8+ T cells than observed in age-matched healthy controls52, thus potentially implying a diminished cytotoxic T cell reserve relevant to anti-tumor immunity and treatment responses.

Exogenous factors

Immunosuppressive components triggering DDR deficits

Immunosuppression is a hallmark of the TME54, where components, including tumor cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), induce DNA damage in effector T cells. In a study by Liu et al.55, treatment of CD4+ and CD8+ T cells with the mouse tumor cell lines E0771, LL/2, and B16F10 notably increased ATM phosphorylation, whereas T cells co-cultured with control NIH/3T3 cells showed minor phosphorylation levels. In addition, increased activation and phosphorylation of other key DDR proteins, including H2AX and checkpoint kinase 2 (CHK2), were documented in T cells treated with tumor cell lines55.

Moreover, Tregs pose a major obstacle to successful tumor immunotherapy56,57 and have been reported to induce DNA damage in effector T cells through glucose competition58. Tregs outcompete effector T cells for glucose uptake by expressing higher levels of glucose transporters GLUT1 and GLUT3. The resultant hypoglycemic microenvironment triggers robust DNA damage in effector CD4+ and CD8+ T cells, as evidenced by the phosphorylation of DDR molecules, including ATM, CHK2, H2AX, and 53BP158.

MDSCs are also crucial immunosuppressive players in the TME that inhibit T cell proliferation and survival59. Interferon-gamma (IFN-γ), secreted by activated T cells, induces Nos2 gene expression in MDSCs and enhances inducible nitric oxide synthase (iNOS) expression, thus increasing nitric oxide (NO) release60. By inducing DNA base deamination and DNA strand breaks, NO compromises CD8+ T cell genomic integrity and activates the p53-mediated apoptotic pathway61.

T cell DNA damage associated with anti-tumor treatment

Inducing DNA damage in cancer cells has long been an effective anti-tumor strategy. Conventional therapies, such as chemotherapy and radiotherapy, eliminate cancer cells by disrupting DNA synthesis in rapidly proliferating cells62. However, these treatments also harm non-cancerous cells and lead to hematologic toxicities such as lymphopenia63. Several frontline chemotherapeutics impose genotoxic stress on T cells. Etoposide, a topoisomerase II inhibitor, impairs replication and transcription, and induces DNA damage even in resting T cells, as evidenced by phosphorylation of ATM, H2AX, and p5364,65. Platinum agents, which constitute the backbone of many first-line regimens, generate bulky DNA adducts and intra-or interstrand crosslinks. Accordingly, cisplatin exposure is associated with increased DNA damage markers and impaired proliferative ability in human peripheral blood lymphocytes66,67. Moreover, other frequently used agents—including alkylating drugs (e.g., cyclophosphamide) that create DNA crosslinks, the microtubule-stabilizing agent paclitaxel, and antimetabolites such as 5-fluorouracil that elicit replication-associated stress and engage ATR-dependent DDR signaling—may also contribute to genotoxicity in T cells15. However, direct evidence quantifying T cell-specific DDR activation remains limited. T cells exhibit high radiosensitivity, and ROS and DNA damage occur immediately after exposure to a 5-Gy dose of radiation and persisting for more than 10 hours68,69. Beyond direct DNA damage induction, concurrent chemoradiotherapy, the first-line treatment for locally advanced cervical cancer, accelerates CD8+ T cell DNA damage by promoting the expansion of atypical chemokine receptor 2 (ACKR2)-positive, concurrently chemoradiotherapy-resistant tumor cells. These tumor cells secrete TGF-β, which in turn drives CD8+ T cell senescence and enhanced DDR70.

Beyond conventional genotoxic treatments such as chemotherapy and radiotherapy, DDR inhibitors (DDRi) have emerged as a critical anti-tumor therapy and determinant of tumor immunogenicity71. DDRi may enhance anti-tumor immunity by improving T cell infiltration, inducing immunogenic cell death in tumor cells, boosting tumor immunogenicity through neoantigen generation, and decreasing immunosuppressive cell infiltration72. However, emerging evidence suggests that DDRi might have inhibitory effects on T cells. The central DDR pathway kinase ATR initiates cellular responses to genomic instability. Clinical observations have revealed that ATR inhibitors (ATRi) decrease circulating monocytes, lymphocytes, and platelets in patients with cancer, thus implying suppression of CD8+ T cell-dependent antitumor immunity73. Regarding PARP inhibitors (PARPi), which exploit synthetic lethality in inducing cell death in homologous recombination-deficient tumors, single-cell data analysis from a clinical trial evaluating neoadjuvant monotherapy with the PARPi niraparib in patients with newly diagnosed ovarian cancer has indicated enriched DNA damage and apoptotic pathways in T cells after treatment74. Mechanistically, PARPi suppresses PARP1 enzymatic activity, thus leading to PARP1 trapping and exacerbating DNA damage accumulation and apoptosis in T cells75. However, given their ability to enhance tumor immunogenicity by promoting cytosolic DNA accumulation and activating the cGAS-STING pathway in tumor cells, DDRi are frequently combined with immune checkpoint blockade in clinical settings. This apparent paradox of direct toxicity to T cells vs. tumor cell-driven immunostimulatory effects underscores the complexity of anti-tumor therapy and highlights the need to consider the integrated effects on the TME when developing novel treatment strategies.

DNA damage during genome editing

Adaptive CAR-T cell therapy is a notable avenue in anti-tumor treatment76. CAR-T cell therapy innovatively uses genetic engineering techniques to modify patients’ autologous T cells to express the specific antigen, thereby achieving precise recognition and efficient elimination of tumor cells77,78. CRISPR-Cas9 genome editing is frequently used to enhance the functionality of CAR-T cells79. However, unforeseen off-target DNA damage prompts major safety concerns. CRISPR/Cas9 has been reported to lead to persistent chromosomal loss and alterations in T cells, including large deletions and chromosomal translocations80. Moreover, T4 DNA polymerase rapidly fills the gaps in DNA strands after cleavage by the CRISPR/Cas9 system, thus circumventing extensive deletions that arise from incomplete DNA strands81.

Effects of DNA damage on T cell fate and function

The effects of DNA damage in T cells depend on the balance between DNA damage and DNA damage repair mechanisms. Most DNA damage occurring during T cell activation can be efficiently repaired27. Other processes, including immunosuppressive TME challenges and anti-tumor treatments, may result in DNA damage accumulation and more severe consequences such as T cell apoptosis. Other effects include reduced T cell cytotoxicity, loss of T cell memory and stemness, enhanced T cell exhaustion, and T cell senescence (Figure 2).

Figure 2
Figure 2

Functional consequences of T cell DNA damage. This schematic summarizes the major cellular and functional outcomes of DNA damage in T cells. (A) Increased apoptosis: Persistent or severe DNA damage activates canonical stress-response pathways, including p53-dependent apoptosis (p53 activation and FAS upregulation), and JNK/p73-dependent apoptosis, thus resulting in cleaved caspase-3 activation. (B) Decreased cytotoxicity: DNA damage disrupts metabolic fitness and effector programming and leads to impaired cytolytic activity against tumor cells. (C) Altered memory/stemness: Activation of cGAS-STING signaling and modulation of pathways such as AKT/mTORC1 influence Tcf7, thereby reshaping memory differentiation and stem-like properties. (D) Enhanced exhaustion: Sustained genomic stress promotes upregulation of inhibitory receptors (including TIM-3, CTLA-4, and PD-1) and epigenetic remodeling, thus reinforcing an exhausted T cell state. (E) Induced senescence: Chronic DNA damage contributes to telomere erosion and the development of a SASP and further limits proliferative ability and functional persistence. AKT, protein kinase B; cGAS, cyclic GMP-AMP synthase; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; FAS, FAS cell surface death receptor; JNK, c-Jun N-terminal kinase; mTORC1, mechanistic target of rapamycin complex 1; p53, tumor protein p53; p73, tumor protein p73; PD-1, programmed cell death protein 1; SASP, senescence-associated secretory phenotype; STING, stimulator of interferon genes; Tcf7, gene of T cell factor 1; TIM-3, T cell immunoglobulin and mucin domain-containing protein 3. Created with BioRender.com.

T cell apoptosis

Because the DDR is a highly orchestrated mechanism that determines cell viability, the influence of DNA damage on cellular fate is complex and critical82. Cells bearing DNA damage are arrested at the G1/S or G2/M cell cycle checkpoints, thus providing a critical temporal window for DNA repair and preventing the transmission of damaged DNA to subsequent cell cycle phases83,84. However, in cases of irreparable DNA damage, cells may undergo irreversible cell death compromising T cell homeostasis. P53 activation and FAS upregulation are frequently observed in DNA-damaged T cells; consequently, these cells are sensitive to P53-dependent apoptosis85. P53-independent apoptosis has also been reported in T cells. In resting T cells with DNA damage, elevated phosphorylation of JNK and P73 indicates JNK/P73-dependent apoptosis35. Moreover, IFN-γ-induced DNA damage-related apoptosis has also been documented, as indicated by the concurrent elevated production of pro-inflammatory IFN-γ and high expression of IFN-γ receptors on the surfaces of damaged T cells86.

Accumulating evidence indicates that susceptibility to DNA damage–induced apoptosis varies across T cell subsets. In the context of activated and resting status, several studies have suggested that targeted DDRi have minimal effects on proliferation-inefficient naive T cells. In contrast, rapidly proliferating effector T cells, the key subset of inflammatory effector cells, are more sensitive to DDRi-induced cell death87. Other studies have indicated that resting T cells are more sensitive to DNA damage in their resting state than in their activated state88,89, because of the induction of DNA repair proteins during T cell activation35. Additionally, DNA damage inducers such as γ-irradiation, ultraviolet light, and anti-CD3/CD28 beads have been reported to enhance cell death in more differentiated T cell subsets, including TEM and TEMRA cells27,90. In contrast, the TSCM subset, which is characterized by elevated DNA repair efficiency, exhibits diminished expression of caspase-3 under DNA damage stress91. This subset-specific vulnerability suggests that genotoxic therapies and DDR-targeting strategies might differentially reshape T cell composition and have direct implications for sustaining durable anti-tumor immunity. Overall, these findings suggest that T cells should not be treated as a single uniform population and highlight the need for a subset-resolved framework in which the sources, tolerance, functional consequences, and mitigation strategies of DNA damage are considered in a subset-specific manner.

T cell cytotoxicity

Beyond effects on survival and differentiation, DNA damage can also rewire key effector programs in T cells by reshaping their cytokine secretion profiles. For example, the accumulation of oxidative DNA damage can accelerate premature exhaustion of T cells, thereby impairing their ability to effectively produce granzyme B (GZMB), IFN-γ, and IL-292. Persistent antigen exposure-induced T cell DNA damage, mediated by upregulation of CD38, leads to diminished cytokine secretion ability and attenuated IFN-γ-mediated immune responses44. Recently, researchers have discovered that oxidative DNA damage in T cells, mediated by the suppression of pyruvate utilization and the enhancement of fatty acid utilization, leads to decreased production of IFN-γ and GZMB93. GATA3, a well-characterized protein in T cell development in the thymus, has also been found to maintain T cell viability and cytotoxicity during DNA damage by promoting mitochondrial biogenesis and forming a complex with PGC1α, NRF2, and ATR94.

T cell memory and stemness

Aberrations in the DDR also reprogram T cell fate decisions by altering the differentiation trajectories of T cells95. The memory subset of T cells is important in prolonged immune responses and correlates with relatively favorable prognosis after immunotherapy96. In ATM−/− mice, accumulation of DNA damage is associated with impeded differentiation of CD8+ T cells into the memory subset. This response might be attributable to the hyperactivation of the AKT and mTORC1 signaling pathways and diminished expression of TCF1 after T cell receptor engagement97. More recently, a novel CD8+ T cell subset characterized by high expression of CD62L and TCF1 with long-term memory capabilities and heightened DNA damage surveillance has been delineated91.

Stem-like T cells, because of their advantageous properties of self-renewal, expansion, and multipotency, also have critical roles in sustaining immune responses98. Emerging evidence indicates that the cGAS-STING pathway, activated by DNA damage and cytosolic DNA accumulation in T cells, is a critical regulator of T cell stemness. The underlying mechanism involves cGAS-STING-dependent type I interferon signaling, which promotes stem cell-like differentiation by upregulating TCF1 expression and suppressing AKT activity in CD8+ T cells99. Importantly, the outcome of T cell-intrinsic STING signaling appears to be dependent on signal strength and duration. Whereas tuned and transient STING activation supports stem-like programs, sustained STING activation elicits an intensified response that engages pro-apoptotic circuitry and drives T cell apoptosis. Mechanistically, in T cells with relatively high STING expression, strong STING signaling activates IRF3 and p53 and induces the BH3-only genes NOXA and PUMA, thereby promoting apoptosis100. Beyond nuclear DNA damage, mitochondrial DNA, which is particularly susceptible to oxidative injury, can leak into the cytosol via mPTP/VDAC channels during mitochondrial stress and provide a potentially persistent source of cGAS ligands101, thereby sustaining STING activation and reshaping downstream functional states in T cells.

T cell exhaustion

An immunosuppressive TME fosters progressive T cell exhaustion, a state sustained by chronic antigen exposure and persistent inhibitory receptor signaling. Accumulating evidence suggests that persistent genomic stress and DNA damage accumulation actively contribute to T cell exhaustion. Using a chemo-optogenetic platform to spatially confine ROS to telomeres in T cells, Rivadeneira et al.102 have demonstrated enrichment in canonical DDR markers (γH2AX and 53BP1) at telomeric regions and concomitant induction of exhaustion-associated phenotypes, including elevated PD-1 and Tim-3 expression, and diminished production of effector cytokines IFN-γ, TNF-α, and IL-2. Moreover, because terminally exhausted T (PD-1hi Tim-3hi) cells display higher levels of telomeric γH2AX than progenitor-exhausted T (PD-1mid Tim-3−) cells, telomere-associated DNA damage escalates with exhaustion progression. Concordantly, Kelliher et al.103 have reported that chronic stimulation accelerates exhaustion by imposing replication stress and promoting the accumulation of DNA strand breaks in an in vitro human CD8+ T cell exhaustion model.

Beyond these direct genotoxic effects, the DDR might influence long-term T cell fate, including exhaustion, through chromatin remodeling and epigenetic regulation. T cell exhaustion is considered a conserved epigenetic state that acquires “epigenetic scars” under persistent antigen exposure104,105. Sustained genotoxic stress and recurrent DDR activation can also induce chromatin remodeling and epigenetic changes leading to persistent changes in transcriptional networks106. Notably, because the chromatin remodeling complex PBAF participates both in chromatin reorganization at DNA breaks and in T cell exhaustion differentiation107,108, DDR-linked chromatin regulators might serve as a bridge between genome maintenance and the epigenetic stabilization of T cell exhaustion.

Notably, emerging evidence reveals that inhibitory receptor signaling, particularly through PD-1 and CTLA-4, might influence T cell genomic stability. Chronic PD-1 signaling enforces a robust cell-cycle restraint in activated T cells by upregulating the CDK inhibitors p27Kip1 and p15INK4B, and suppressing the key cell-cycle regulator Cdc25A, thereby limiting T cell proliferation109. In parallel, transcriptomic profiling of PD-1-stimulated human T cell subsets has shown coordinated modulation of gene expression associated with DNA replication and cell-cycle phase transitions, in agreement with persistent checkpoint signaling reshaping the proliferative and genome integrity of T cells110. Additionally, CTLA-4 promotes ATM activation by associating with its inhibitory protein phosphatase 2A (PP2A) in T cells, thereby enhancing downstream DDR signaling and increasing T cell sensitivity to DNA damage-induced apoptosis111.

Together, these observations suggest a potential feedback loop in which DNA damage promotes exhausted states, whereas sustained checkpoint signaling modulates cell-cycle entry and DDR ability, thereby influencing the accumulation and consequences of genomic lesions under chronic stress in TME.

T cell senescence

The association between DNA damage and cellular senescence has been well established in various cell types112. In T cells, senescence refers to the progressive dysfunction of adaptive immunity113. Hence, preserving T cell genomic stability and limiting DNA damage might be important for mitigating T cell senescence and strengthening anti-tumor immune responses. DDR gene alteration is a critical factor promoting cellular senescence. Transplantation of hematopoietic stem/progenitor cells from ATM wild-type mice into A-T (ATM−/−) mice has been found to delay the aging process. After a 6-month post-transplantation period, ATM−/− mice begin to exhibit signs of T cell senescence. In contrast, non-transplanted ATM−/− mice usually succumb at 3-4 months of age, before the manifestation of T cell senescent traits114.

Within the TME, immunosuppressive Treg-promoted DNA damage is closely associated with senescence in T cells, primarily via activation of the ATM-mediated DDR, coordinated with MAPK signaling and transcription factors such as signal transducer and activator of transcription 1 (STAT1) and STAT358. Activated MAPKs can also lead to the activation of p38, JNK, and ERK, which suppress telomerase activity, compromise telomere maintenance, and cause dysfunctional T cell proliferation and senescence115. Notably, impaired telomerase function and the ensuing telomere erosion can themselves provoke a persistent DDR at chromosome ends116, and consequently might further exacerbate Treg-driven genomic instability and accelerate the decline in T cell antitumor function. Activated p38 and ERK, in cooperation with STAT1/3, substantially increase the expression of cyclin-dependent kinase inhibitors such as p21, p16, and p53, thus preventing T cell proliferation and leading to tumor-associated T cell senescence117,118. Additionally, activated p38 and JNK inhibit the expression and activity of key components of TCR signaling, as well as the costimulatory receptors CD27 and CD28, thereby resulting in the formation of T cell-specific senescence-associated secretory phenotypes (SASPs)119. Notably, senescent T cells have a unique SASP producing high amounts of proinflammatory cytokines such as IL-2, IL-6, IL-8, TNF, and IFN-γ, which can induce premature T cell senescence, as well as the suppressive mediators such as IL-10 and TGF-β, thereby reshaping TME120. These SASP factors can dampen effector T cell and dendritic-cell functions; promote the expansion of Tregs and suppressive myeloid populations; and ultimately collectively amplify immune suppression113. Beyond immune modulation, SASP has been implicated in directly supporting malignant phenotypes, including enhanced tumor cell growth and epithelial-mesenchymal transition; therefore, T cell senescence is an emerging target for tumor immunotherapy121.

Treatment implications

T cell DNA damage as an indicator of treatment efficacy

Despite the many deleterious consequences of DNA damage in T cells, recent studies including clinical observations have revealed that the severity of DNA damage in T cells or the expression levels of key DDR molecules might provide promising biomarkers for the efficacy of immunotherapies and DDRi (Figure 3). In a clinical study testing PD-1 blockade in uterine cancer, T cell proliferation peaked at 2 weeks after anti-PD-1 therapy, and a strong correlation was observed between the expression of pATM and PD-1 in CD8+ T cells. Patients with uterine cancer with high pATM expression tend to have prolonged survival after PD-1 blockade treatment27. In another neoadjuvant trial assessing PARPi niraparib monotherapy in patients with newly diagnosed ovarian cancer, single-cell analysis of paired pre- and post-treatment samples indicated an association between elevated T cell DNA damage and diminished progression-free survival74.

Figure 3
Figure 3

DNA damage as a biomarker of treatment efficacy. This schematic summarizes representative clinical contexts in which DNA damage in T cells is associated with therapeutic efficacy. (A) PD-1 blockade and pATM in T cells: In patients with uterine cancer treated with anti-PD-1 therapy, Ki67+ CD8+ T cell proliferation peaks approximately 2 weeks after the start of treatment. Elevated pATM levels in these T cells correlate with different clinical outcomes. (B) PARPi monotherapy and T cell DNA damage: In newly diagnosed ovarian cancer, PARPi (e.g., niraparib) increases DNA damage in T cells, which in turn correlates with poorer therapeutic response. (C) Allo-SCT and 8-OHdG in donor T cells: After allo-SCT for hematologic malignancies, oxidative DNA damage in donor-derived T cells, indicated by increased 8-OHdG, is associated with T cell exhaustion characterized by upregulation of inhibitory receptors such as PD-1, CTLA-4, KLRG1, and LAG-3. (D) Anti-CD19 CAR-T in DLBCL: In DLBCL treated with anti-CD19 CAR-T therapy, T cells from CRs have less DNA damage and apoptosis, whereas those from non-CRs exhibit more genomic damage and higher apoptotic susceptibility. 8-OHdG, 8-hydroxy-2′-deoxyguanosine; allo-SCT, allogeneic stem cell transplantation; CAR-T, chimeric antigen receptor T cell; CRs, complete responders; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; DLBCL, diffuse large B-cell lymphoma; Ki67, marker of proliferation; KLRG1, killer cell lectin-like receptor G1; LAG-3, lymphocyte activation gene-3; PARPi, poly (ADP-ribose) polymerase inhibitor; pATM, phosphorylated ataxia-telangiectasia mutated; PD-1, programmed cell death protein 1. Created with BioRender.com.

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-SCT), a curative therapeutic option for many patients with hematologic malignancies, is highly dependent on the tumor-killing efficacy of donor T cells122. The compound 8-OHdG has been established as a biomarker for oxidative DNA damage in T cells from the peripheral blood of 66 patients undergoing allo-SCT123. T cells with high 8-OHdG expression exhibit signs of sustained activation and premature exhaustion, which are associated with relapse and shortened survival after allo-SCT treatment92. For patients with diffuse large B-cell lymphoma, single-cell sequencing comprehensively comparing the differences between complete responders (CR) and non-complete responders (non-CR) after anti-CD19 CAR-T cell therapy has revealed enrichment in DNA damage and p53-mediated intrinsic apoptosis pathways in the non-CR group; consequently, intrinsic DDR defects in T cells might lead to suboptimal CAR-T responses124.

Strategies to alleviate T cell DNA damage

In vivo therapeutic modulation

From a treatment perspective, several targeted therapeutic strategies are under investigation to alleviate T cell dysfunction caused by DNA damage in various circumstances (Figure 4). These approaches, despite having been established primarily in preclinical models, offer potential translational avenues. For example, exogenous supplementation with the NAD precursor β-nicotinamide mononucleotide (NMN) or limiting NAD consumption through CD38 blockade has been shown to restore PARP-mediated DNA damage repair and enhance T cell activation, expansion, and cytotoxicity in mouse models. This response is achieved by rescuing the CD38-mediated overconsumption of NAD+, which otherwise drives ROS accumulation and failure of PARP-mediated DNA damage repair during T cell activation44. Notably, however, NAD-boosting strategies remain largely investigational in oncology, and only limited early stage clinical exploration has been conducted to date125.

Figure 4
Figure 4

Strategies to mitigate T cell DNA damage. This schematic summarizes potential therapeutic strategies to decrease DNA damage in T cells and enhance their anti-tumor function. (A) Metabolic reprogramming: Approaches including CD38 inhibition or NMN supplementation increase intracellular NAD+ levels in T cells, thereby enhancing PARP-mediated DNA repair, decreasing mitochondrial ROS, and preserving telomere integrity. (B) Targeting TME immunosuppression: Targeting immunosuppressive components of the TME can alleviate DNA damage-inducing stress in T cells. MDSCs generate NO via iNOS, whereas Tregs promote glucose deprivation through metabolic competition. Strategies such as iNOS inhibition, glucose supplementation, and modulation of ATM/p38 inhibition might help restore T cell metabolic fitness and genomic stability. (C) Optimizing DDRi therapy: Approaches such as sequential DDRi administration, gene-editing strategies targeting PARP1, or the use of non-trapping PARPi might limit excessive DNA damage in T cells. (D) Ex vivo manufacturing optimization: Improvements in ex vivo manufacturing protocols for adoptive T cell therapies can further minimize genomic stress. Novel protocols incorporating optimized activation conditions, isotonic electroporation buffers, and CRISPR editing decrease DNA damage during cell engineering and expansion, thereby increasing the functional quality of therapeutic T cells. ATM, ataxia-telangiectasia mutated; Cas9, CRISPR-associated protein 9; CRISPR, clustered regularly interspaced short palindromic repeats; DDRi, DNA damage response inhibitor; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MDSCs, myeloid-derived suppressor cells; NAD+, nicotinamide adenine dinucleotide; NMN, β-nicotinamide mononucleotide; NO, nitric oxide; PARP, poly(ADP-ribose) polymerase; PARP1, poly (ADP-ribose) polymerase 1; PARPi, poly (ADP-ribose) polymerase inhibitor; p38, p38 mitogen-activated protein kinase; RNP, ribonucleoprotein; ROS, reactive oxygen species; TME, tumor microenvironment; Tregs, regulatory T cells. Created with BioRender.com.

To alleviate immunosuppressive TME-induced T cell DNA damage, multiple targeted approaches have been proposed to preserve T cell viability and cytotoxicity. In preclinical settings, the incorporation of iNOS inhibitors has been demonstrated to ameliorate T cell apoptosis and mitigate DNA damage caused by MDSC-secreted NO60. Clinically, NO synthase inhibition has entered early phase trials125, and further validation in larger cohorts remains necessary. Furthermore, to diminish T cell DNA damage instigated by ATM and MAPK pathway activation by tumor cells and Tregs, concomitant administration of ATM inhibitors or p38 inhibitors in conjunction with adoptive T cell transfer, or pretreating T cells with ATM inhibitors before adoptive transfer, has shown benefit in tumor-bearing mouse models55,58. Moreover, inhibition of ATM or MAPK acts synergistically with ICBs in suppressing T cell DNA damage and enhancing antitumor immunity in preclinical models55, whereas inhibitors targeting ATM or p38/MAPK are currently being evaluated primarily as tumor-directed agents49,126. However, whether they can be deployed safely to protect T cells in patients requires further evaluation. Glucose supplementation is also under consideration, because it might alleviate glucose competition in the TME between Treg and effector T cells, thereby relieving DNA damage58.

The differential vulnerability of T cells and tumor cells to DNA damage provides a rationale for therapeutic strategies that selectively target cancer cells while preserving T cell function. T cells typically maintain intact DDR pathways, possess relatively low baseline replication stress15, and retain functional p53-mediated apoptotic checkpoints127. In contrast, tumor cells often exhibit DDR defects128, persistent replication stress due to oncogenic signaling129,130, and p53 mutations that permit continued proliferation despite DNA damage. These distinctions create a potential therapeutic window wherein DDRi might be optimized to maximize tumor cytotoxicity and immunogenicity while minimizing T cell-intrinsic toxicity. This balance is particularly critical, given the increasing clinical use of DDRi combined with immune checkpoint blockade.

Conceptually, this window might be widened through several approaches. First, sequential administration of agents targeting different DDR molecules might provide intervals during which T cells can repair lesions and restore fitness, whereas tumor cells, burdened by higher basal replication stress, remain vulnerable across dosing cycles131,132. Second, dose optimization might also help enhance tolerability. Lower starting doses, toxicity-guided individualization, and intermittent or pulsed dosing have been used to mitigate cumulative hematologic toxicities in clinical practice, as illustrated by the routine use of dose interruptions/reductions for PARP inhibitors and the use of intermittent schedules for DDR kinase inhibitors in early phase development133,134. Finally, more precise immune-sparing strategies might be achievable through genetic ablation of PARP1 or site-specific editing of PARP1 in T cells, to mitigate PARPi-induced DNA damage in T cells74, although clinical translation remains to be established. Additionally, the application of PARPi with no-trapping activity could also be considered an option for combination therapy with immunotherapy and therefore warrants further evaluation74,135.

Ex vivo manufacturing optimization

Beyond in vivo pharmacologic modulation, ex vivo manufacturing optimization focuses on decreasing genotoxicity introduced by activation, electroporation, and genome-editing procedures during cell product generation of T cells. Investigations have revealed a novel protocol that introduces Cas9 RNP before T cell activation and stimulation. Compared with the conventional protocol, which stimulates T cells before gene editing, this novel protocol robustly decreases chromosomal loss, thereby mitigating the genotoxicity for clinical applications80. In addition, an innovative gene editing tool, CasPLUS, which incorporates DNA polymerase from bacteriophage T4, has promise in preventing deleterious target DNA damage81. Through screening of electroporation conditions, researchers have also discovered that use of an isotonic buffer enhances both the viability and quantity of CAR-T cells, as well as their in vivo anti-tumor activity136.

Conclusions

As the correlation between DNA damage and the immune response has been established, and the clinical applications of DDRi have expanded, the role of DNA damage in T cells has become increasingly important. However, T cell-intrinsic DNA damage is a distinct and previously underappreciated determinant with substantial effects on anti-tumor therapy. The DNA damage burden and DDR activity in T cells are not merely unavoidable passive byproducts of treatment but instead actively shape T cell survival, differentiation, and effector function, thereby influencing therapeutic responses. This view reframes T cell genomic integrity as a treatment-coupled determinant of immune efficacy. Through diverse mechanisms, including oxidative stress, replication stress, inflammatory signaling, and TME crosstalk, T cell DNA damage interacts with and modulates the effects of many anti-tumor treatments, including radiotherapy, chemotherapy, and DDR-targeted therapies.

Importantly, viewing T cell DNA damage as a therapeutic variable has clear translational relevance. First, T cell DNA damage and DDR genes have promise as measurable biomarkers for patient stratification, dynamic monitoring of anti-tumor immunity, and response prediction. Second, this framework highlights the need to develop immune-preserving genotoxic strategies, not by weakening tumor-directed cytotoxicity but by optimizing dosing paradigms or rational combinations to limit the accumulation of damage in T cells. Importantly, T cells within the TME are highly heterogeneous and differ in their susceptibility to DNA damage, thereby underscoring the need for tailored protective strategies to selectively decrease genotoxic stress in vulnerable subsets. Finally, future clinical studies might benefit from prospectively incorporating relevant markers, such as DNA repair ability and damage-associated phenotypes in T cell subsets, into trial design to enable regimens that effectively control tumors while preserving functional T cell immunity.

In summary, T cell DNA damage is an emerging field with direct therapeutic relevance and substantial translational potential, which might provide a practical path to improving the efficacy, durability, and safety of anti-tumor treatments.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Jiahao Liu, Qinglei Gao.

Collected the data: Xiaofei Jiao, Yiyang Shen, Yixuan Tang.

Contributed data or analysis tools: Xiaofei Jiao, Yiyang Shen, Yixuan Tang.

Performed the analysis: Xiaofei Jiao, Yiyang Shen, Yixuan Tang, Jiahao Liu.

Wrote the paper: Xiaofei Jiao, Jiahao Liu.

  • Received January 9, 2026.
  • Accepted March 18, 2026.

References

  1. 1.↵
    2. Siegel RL,
    3. Giaquinto AN,
    4. Jemal A.
    Cancer statistics, 2024. CA Cancer J Clin. 2024; 74: 12–49.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Islami F,
    3. Arias G,
    4. Lee D,
    5. Wiese D,
    6. Baeker Bispo J,
    7. Yabroff KR, et al.
    American Cancer Society’s report on the status of cancer disparities in the United States, 2025. CA Cancer J Clin. 2026; 76: e70045.
  3. 3.↵
    2. Blucher AS,
    3. Choonoo G,
    4. Kulesz-Martin M,
    5. Wu G,
    6. McWeeney SK.
    Evidence-based precision oncology with the cancer targetome. Trends Pharmacol Sci. 2017; 38: 1085–99.
    OpenUrlCrossRef
  4. 4.
    2. Repetto M,
    3. Fernandez N,
    4. Drilon A,
    5. Chakravarty D.
    Precision oncology: 2024 in review. Cancer Discov. 2024; 14: 2332–45.
    OpenUrlPubMed
  5. 5.↵
    2. Sharma P,
    3. Siddiqui BA,
    4. Anandhan S,
    5. Yadav SS,
    6. Subudhi SK,
    7. Gao J, et al.
    The next decade of immune checkpoint therapy. Cancer Discov. 2021; 11: 838–57.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    2. Albelda SM.
    CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat Rev Clin Oncol. 2024; 21: 47–66.
    OpenUrlCrossRefPubMed
  7. 7.
    2. Nie Y.
    Breaking barriers: the emerging promise of CAR-T cell therapy in solid tumors. Holist Integr Oncol. 2025; 4: 70.
    OpenUrl
  8. 8.↵
    2. Ambrosini M,
    3. Manca P,
    4. Nasca V,
    5. Sciortino C,
    6. Ghelardi F,
    7. Seligmann JF, et al.
    Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers. Nat Rev Clin Oncol. 2025; 22: 385–407.
    OpenUrlPubMed
  9. 9.↵
    2. Lorusso D,
    3. Xiang Y,
    4. Hasegawa K,
    5. Scambia G,
    6. Leiva M,
    7. Ramos-Elias P, et al.
    Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024; 403: 1341–50.
    OpenUrlCrossRefPubMed
  10. 10.
    2. Pointer KB,
    3. Pitroda SP,
    4. Weichselbaum RR.
    Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer. 2022; 8: 9–20.
    OpenUrlPubMed
  11. 11.↵
    2. Eskander RN,
    3. Sill MW,
    4. Beffa L,
    5. Moore RG,
    6. Hope JM,
    7. Musa FB, et al.
    Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023; 388: 2159–70.
    OpenUrlCrossRefPubMed
  12. 12.↵
    2. Cheng X,
    3. Shen J,
    4. Xu J,
    5. Zhu J,
    6. Xu P,
    7. Wang Y, et al.
    In vivo clinical molecular imaging of T cell activity. Trends Immunol. 2023; 44: 1031–45.
    OpenUrlPubMed
  13. 13.↵
    2. Waldman AD,
    3. Fritz JM,
    4. Lenardo MJ.
    A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020; 20: 651–68.
    OpenUrlCrossRefPubMed
  14. 14.↵
    2. Jackson SP,
    3. Bartek J.
    The DNA-damage response in human biology and disease. Nature. 2009; 461: 1071–8.
    OpenUrlCrossRefPubMed
  15. 15.↵
    2. Groelly FJ,
    3. Fawkes M,
    4. Dagg RA,
    5. Blackford AN,
    6. Tarsounas M.
    Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2023; 23: 78–94.
    OpenUrlCrossRefPubMed
  16. 16.↵
    2. Huang R,
    3. Zhou PK.
    DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther. 2021; 6: 254.
    OpenUrlPubMed
  17. 17.↵
    2. Zeng Y,
    3. Arisa O,
    4. Peer CJ,
    5. Fojo A,
    6. Figg WD.
    PARP inhibitors: a review of the pharmacology, pharmacokinetics, and pharmacogenetics. Semin Oncol. 2024; 51: 19–24.
    OpenUrlCrossRefPubMed
  18. 18.↵
    2. Lord CJ,
    3. Ashworth A.
    PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355: 1152–8.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    2. Chabanon RM,
    3. Rouanne M,
    4. Lord CJ,
    5. Soria JC,
    6. Pasero P,
    7. Postel-Vinay S.
    Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat Rev Cancer. 2021; 21: 701–17.
    OpenUrlCrossRefPubMed
  20. 20.↵
    2. Ishikawa H,
    3. Barber GN.
    STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455: 674–8.
    OpenUrlCrossRefPubMed
  21. 21.
    2. Shen J,
    3. Zhao W,
    4. Ju Z,
    5. Wang L,
    6. Peng Y,
    7. Labrie M, et al.
    PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2019; 79: 311–9.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    2. Ding L,
    3. Kim HJ,
    4. Wang Q,
    5. Kearns M,
    6. Jiang T,
    7. Ohlson CE, et al.
    PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 2018; 25: 2972–80.e5.
    OpenUrlCrossRefPubMed
  23. 23.↵
    2. Rolfo C,
    3. Giovannetti E,
    4. Martinez P,
    5. McCue S,
    6. Naing A.
    Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer. NPJ Precis Oncol. 2023; 7: 26.
    OpenUrlPubMed
  24. 24.↵
    2. Galluzzi L,
    3. Brackett S,
    4. Johnson N.
    ZBP1 links infections to cancer immunotherapy. Cell Res. 2026; 36: 177–8.
    OpenUrlPubMed
  25. 25.↵
    2. Concannon K,
    3. Morris BB,
    4. Gay CM,
    5. Byers LA.
    Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control. Mol Cell. 2023; 83: 660–80.
    OpenUrlPubMed
  26. 26.↵
    2. Liu J,
    3. Jiao X,
    4. Ma D,
    5. Fang Y,
    6. Gao Q.
    CAR-T therapy and targeted treatments: emerging combination strategies in solid tumors. Med. 2024; 5: 530–49.
    OpenUrlPubMed
  27. 27.↵
    2. Muroyama Y,
    3. Manne S,
    4. Wellhausen N,
    5. Oldridge DA,
    6. Greenplate AR,
    7. Chilukuri L, et al.
    Induction of a CD8 T cell intrinsic DNA damage and repair response is associated with clinical response to PD-1 blockade in uterine cancer. bioRxiv. 2022.
  28. 28.↵
    2. Park SH,
    3. Kim Y,
    4. Ra JS,
    5. Wie MW,
    6. Kang MS,
    7. Kang S, et al.
    Timely termination of repair DNA synthesis by ATAD5 is important in oxidative DNA damage-induced single-strand break repair. Nucleic Acids Res. 2021; 49: 11746–64.
    OpenUrlPubMed
  29. 29.↵
    2. Sengupta S,
    3. Wang H,
    4. Yang C,
    5. Szczesny B,
    6. Hegde ML,
    7. Mitra S.
    Ligand-induced gene activation is associated with oxidative genome damage whose repair is required for transcription. Proc Natl Acad Sci U S A. 2020; 117: 22183–92.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    2. Sokolov MV,
    3. Smilenov LB,
    4. Hall EJ,
    5. Panyutin IG,
    6. Bonner WM,
    7. Sedelnikova OA.
    Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts. Oncogene. 2005; 24: 7257–65.
    OpenUrlCrossRefPubMed
  31. 31.↵
    2. Lyu YL,
    3. Kerrigan JE,
    4. Lin CP,
    5. Azarova AM,
    6. Tsai YC,
    7. Ban Y, et al.
    Topoisomerase IIβ–mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007; 67: 8839–46.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    2. Ström CE,
    3. Johansson F,
    4. Uhlén M,
    5. Szigyarto CA,
    6. Erixon K,
    7. Helleday T.
    Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate. Nucleic Acids Res. 2011; 39: 3166–75.
    OpenUrlCrossRefPubMed
  33. 33.↵
    2. Chin Sang C,
    3. Moore G,
    4. Tereshchenko M,
    5. Zhang H,
    6. Nosella ML,
    7. Dasovich M, et al.
    PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation. EMBO Rep. 2024; 25: 5635–66.
    OpenUrlPubMed
  34. 34.↵
    2. Balmus G,
    3. Pilger D,
    4. Coates J,
    5. Demir M,
    6. Sczaniecka-Clift M,
    7. Barros AC, et al.
    ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks. Nat Commun. 2019; 10: 87.
    OpenUrlCrossRefPubMed
  35. 35.↵
    2. Hu Q,
    3. Xie Y,
    4. Ge Y,
    5. Nie X,
    6. Tao J,
    7. Zhao Y.
    Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway. Cell Death Dis. 2018; 9: 662.
    OpenUrlCrossRefPubMed
  36. 36.↵
    2. Ma K,
    3. Xu Y,
    4. Cheng H,
    5. Tang K,
    6. Ma J,
    7. Huang B.
    T cell-based cancer immunotherapy: opportunities and challenges. Sci Bull (Beijing). 2025; 70: 1872–90.
    OpenUrlPubMed
  37. 37.↵
    2. Chopp L,
    3. Redmond C,
    4. O’Shea JJ,
    5. Schwartz DM.
    From thymus to tissues and tumors: a review of T-cell biology. J Allergy Clin Immunol. 2023; 151: 81–97.
    OpenUrl
  38. 38.↵
    2. Tanaka T,
    3. Kajstura M,
    4. Halicka HD,
    5. Traganos F,
    6. Darzynkiewicz Z.
    Constitutive histone H2AX phosphorylation and ATM activation are strongly amplified during mitogenic stimulation of lymphocytes. Cell Prolif. 2007; 40: 1–13.
    OpenUrlPubMed
  39. 39.↵
    2. Peng HY,
    3. Lucavs J,
    4. Ballard D,
    5. Das JK,
    6. Kumar A,
    7. Wang L, et al.
    Metabolic reprogramming and reactive oxygen species in T cell immunity. Front Immunol. 2021; 12: 652687.
  40. 40.↵
    2. Franchina DG,
    3. Dostert C,
    4. Brenner D.
    Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol. 2018; 39: 489–502.
    OpenUrlCrossRefPubMed
  41. 41.↵
    2. Kwon J,
    3. Shatynski KE,
    4. Chen H,
    5. Morand S,
    6. de Deken X,
    7. Miot F, et al.
    The nonphagocytic NADPH oxidase Duox1 mediates a positive feedback loop during T cell receptor signaling. Sci Signal. 2010; 3: ra59.
  42. 42.
    2. Jackson SH,
    3. Devadas S,
    4. Kwon J,
    5. Pinto LA,
    6. Williams MS.
    T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol. 2004; 5: 818–27.
    OpenUrlCrossRefPubMed
  43. 43.↵
    2. Wahl DR,
    3. Byersdorfer CA,
    4. Ferrara JL,
    5. Opipari AW Jr.,
    6. Glick GD.
    Distinct metabolic programs in activated T cells: opportunities for selective immunomodulation. Immunol Rev. 2012; 249: 104–15.
    OpenUrlCrossRefPubMed
  44. 44.↵
    2. Montali I,
    3. Ceccatelli Berti C,
    4. Morselli M,
    5. Acerbi G,
    6. Barili V,
    7. Pedrazzi G, et al.
    Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B. J Hepatol. 2023; 79: 50–60.
    OpenUrlPubMed
  45. 45.↵
    2. Wang Y,
    3. Fu Z,
    4. Li X,
    5. Liang Y,
    6. Pei S,
    7. Hao S, et al.
    Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation. Immunity. 2021; 54: 632–47.e9.
    OpenUrlCrossRefPubMed
  46. 46.↵
    2. Riabinska A,
    3. Lehrmann D,
    4. Jachimowicz RD,
    5. Knittel G,
    6. Fritz C,
    7. Schmitt A, et al.
    ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia. 2020; 34: 771–86.
    OpenUrlCrossRefPubMed
  47. 47.
    2. Zheng S,
    3. Song J,
    4. Linghu D,
    5. Yang R,
    6. Liu B,
    7. Xue Z, et al.
    Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity. Int J Biol Sci. 2023; 19: 981–93.
    OpenUrlPubMed
  48. 48.
    2. Obr A,
    3. Malarikova D,
    4. Kriegova E,
    5. Urbankova H,
    6. Zemanova Z,
    7. Manakova J, et al.
    Fundamental prognostic difference of ATM gene mutation and deletion in newly diagnosed mantle cell lymphoma. Mol Med. 2025; 31: 306.
    OpenUrlPubMed
  49. 49.↵
    2. Lee JH.
    Targeting the ATM pathway in cancer: opportunities, challenges and personalized therapeutic strategies. Cancer Treat Rev. 2024; 129: 102808.
  50. 50.↵
    2. Rozenbaum M,
    3. Fluss R,
    4. Marcu-Malina V,
    5. Sarouk I,
    6. Meir A,
    7. Elitzur S, et al.
    Genotoxicity associated with retroviral CAR transduction of ATM-deficient T cells. Blood Cancer Discov. 2024; 5: 267–75.
    OpenUrlPubMed
  51. 51.↵
    2. Mak TW,
    3. Hakem A,
    4. McPherson JP,
    5. Shehabeldin A,
    6. Zablocki E,
    7. Migon E, et al.
    Brca1 required for T cell lineage development but not TCR loci rearrangement. Nat Immunol. 2000; 1: 77–82.
    OpenUrlCrossRefPubMed
  52. 52.↵
    2. Wu B,
    3. Qi L,
    4. Chiang HC,
    5. Pan H,
    6. Zhang X,
    7. Greenbaum A, et al.
    BRCA1 deficiency in mature CD8+ T lymphocytes impairs antitumor immunity. J Immunother Cancer. 2023; 11: e005852.
  53. 53.↵
    2. Jeong JH,
    3. Jo A,
    4. Park P,
    5. Lee H,
    6. Lee HO.
    Brca2 deficiency leads to T cell loss and immune dysfunction. Mol Cells. 2015; 38: 251–8.
    OpenUrlCrossRefPubMed
  54. 54.↵
    2. Tang T,
    3. Huang X,
    4. Zhang G,
    5. Hong Z,
    6. Bai X,
    7. Liang T.
    Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduct Target Ther. 2021; 6: 72.
    OpenUrlPubMed
  55. 55.↵
    2. Liu X,
    3. Si F,
    4. Bagley D,
    5. Ma F,
    6. Zhang Y,
    7. Tao Y, et al.
    Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J Immunother Cancer. 2022; 10: e005020.
  56. 56.↵
    2. Kumagai S,
    3. Itahashi K,
    4. Nishikawa H.
    Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine. Nat Rev Clin Oncol. 2024; 21: 337–53.
    OpenUrlPubMed
  57. 57.↵
    2. Wen Y,
    3. Xia Y,
    4. Yang X,
    5. Li H,
    6. Gao Q.
    CCR8: a promising therapeutic target against tumor-infiltrating regulatory T cells. Trends Immunol. 2025; 46: 153–65.
    OpenUrlPubMed
  58. 58.↵
    2. Liu X,
    3. Mo W,
    4. Ye J,
    5. Li L,
    6. Zhang Y,
    7. Hsueh EC, et al.
    Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat Commun. 2018; 9: 249.
    OpenUrlPubMed
  59. 59.↵
    2. Ibrahim A,
    3. Mohamady Farouk Abdalsalam N,
    4. Liang Z,
    5. Kashaf Tariq H,
    6. Li R,
    7. O Afolabi L, et al.
    MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy. Cancer Gene Ther. 2025; 32: 371–92.
    OpenUrlCrossRefPubMed
  60. 60.↵
    2. Cartwright ANR,
    3. Suo S,
    4. Badrinath S,
    5. Kumar S,
    6. Melms J,
    7. Luoma A, et al.
    Immunosuppressive myeloid cells induce nitric oxide-dependent DNA damage and p53 pathway activation in CD8+ T cells. Cancer Immunol Res. 2021; 9: 470–85.
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    2. Caulfield JL,
    3. Wishnok JS,
    4. Tannenbaum SR.
    Nitric oxide-induced deamination of cytosine and guanine in deoxynucleosides and oligonucleotides. J Biol Chem. 1998; 273: 12689–95.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    2. Reuvers TGA,
    3. Kanaar R,
    4. Nonnekens J.
    DNA damage-inducing anticancer therapies: from global to precision damage. Cancers (Basel). 2020; 12: 2098.
    OpenUrlPubMed
  63. 63.↵
    2. Cytlak UM,
    3. Dyer DP,
    4. Honeychurch J,
    5. Williams KJ,
    6. Travis MA,
    7. Illidge TM.
    Immunomodulation by radiotherapy in tumour control and normal tissue toxicity. Nat Rev Immunol. 2022; 22: 124–38.
    OpenUrlPubMed
  64. 64.↵
    2. Korwek Z,
    3. Sewastianik T,
    4. Bielak-Zmijewska A,
    5. Mosieniak G,
    6. Alster O,
    7. Moreno-Villanueva M, et al.
    Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells. DNA Repair (Amst). 2012; 11: 864–73.
    OpenUrlCrossRefPubMed
  65. 65.↵
    2. El-Far AH,
    3. Elfadadny A,
    4. Ragab RF,
    5. Hamada R,
    6. Elbadawy M,
    7. Fu J.
    Combination of approved chemotherapeutics and natural products for topoisomerase II targeting: efficacy and safety in cancer therapy. Holist Integr Oncol. 2025; 4: 69.
    OpenUrl
  66. 66.↵
    2. Sak A,
    3. Grehl S,
    4. Engelhard M,
    5. Wierlemann A,
    6. Kaelberlah HP,
    7. Erichsen P, et al.
    Long-term in vivo effects of cisplatin on γ-H2AX foci signaling in peripheral lymphocytes of tumor patients after irradiation. Clin Cancer Res. 2009; 15: 2927–34.
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    2. Zahnreich S,
    3. Bhatti A,
    4. Ahmad B,
    5. Drabke S,
    6. Kaufmann J,
    7. Schmidberger H.
    Effects of cisplatin on the radiation response and DNA damage markers in peripheral blood lymphocytes ex vivo. Cells. 2025; 14: 682.
    OpenUrl
  68. 68.↵
    2. Ogawa Y,
    3. Kobayashi T,
    4. Nishioka A,
    5. Kariya S,
    6. Hamasato S,
    7. Seguchi H, et al.
    Radiation-induced reactive oxygen species formation prior to oxidative DNA damage in human peripheral T cells. Int J Mol Med. 2003; 11: 149–52.
    OpenUrlPubMed
  69. 69.↵
    2. Ogawa Y,
    3. Kobayashi T,
    4. Nishioka A,
    5. Kariya S,
    6. Hamasato S,
    7. Seguchi H, et al.
    Radiation-induced oxidative DNA damage, 8-oxoguanine, in human peripheral T cells. Int J Mol Med. 2003; 11: 27–32.
    OpenUrlPubMed
  70. 70.↵
    2. Dai D,
    3. Pei Y,
    4. Zhu B,
    5. Wang D,
    6. Pei S,
    7. Huang H, et al.
    Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and cervical cancer recurrence. Cell Rep Med. 2024; 5: 101550.
  71. 71.↵
    2. Drew Y,
    3. Zenke FT,
    4. Curtin NJ.
    DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications. Nat Rev Drug Discov. 2025; 24: 19–39.
    OpenUrlCrossRefPubMed
  72. 72.↵
    2. Szmyd R,
    3. Gee HE,
    4. Cesare AJ.
    DNA-repair-driven cell death compels us to rethink cancer therapies. Nat Rev Mol Cell Biol. 2025; 26: 643–4.
    OpenUrlPubMed
  73. 73.↵
    2. Kim ST,
    3. Smith SA,
    4. Mortimer P,
    5. Loembé AB,
    6. Cho H,
    7. Kim KM, et al.
    Phase I study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer. Clin Cancer Res. 2021; 27: 4700–9.
    OpenUrlAbstract/FREE Full Text
  74. 74.↵
    2. Liu J,
    3. Jiao X,
    4. Mu W,
    5. Li H,
    6. Xia Y,
    7. Wu Y, et al.
    Mitigating T cell DNA damage during PARP inhibitor treatment enhances antitumor efficacy. Sci Transl Med. 2025; 17: eadr5861.
  75. 75.↵
    2. Gopal AA,
    3. Fernandez B,
    4. Delano J,
    5. Weissleder R,
    6. Dubach JM.
    PARP trapping is governed by the PARP inhibitor dissociation rate constant. Cell Chem Biol. 2024; 31: 1373–82.e10.
    OpenUrlPubMed
  76. 76.↵
    2. Zugasti I,
    3. Espinosa-Aroca L,
    4. Fidyt K,
    5. Mulens-Arias V,
    6. Diaz-Beya M,
    7. Juan M, et al.
    CAR-T cell therapy for cancer: current challenges and future directions. Signal Transduct Target Ther. 2025; 10: 210.
    OpenUrlPubMed
  77. 77.↵
    2. Li J,
    3. Liu C,
    4. Zhang P,
    5. Shen L,
    6. Qi C.
    Optimizing CAR T cell therapy for solid tumours: a clinical perspective. Nat Rev Clin Oncol. 2025; 22: 953–68.
    OpenUrlPubMed
  78. 78.↵
    2. Petri K,
    3. D’Ippolito E,
    4. Künkele A,
    5. Köhl U,
    6. Busch DH,
    7. Einsele H, et al.
    Next-generation T cell immunotherapies engineered with CRISPR base and prime editing: challenges and opportunities. Nat Rev Clin Oncol. 2025; 22: 902–23.
    OpenUrlPubMed
  79. 79.↵
    2. Datlinger P,
    3. Pankevich EV,
    4. Arnold CD,
    5. Pranckevicius N,
    6. Lin J,
    7. Romanovskaia D, et al.
    Systematic discovery of CRISPR-boosted CAR T cell immunotherapies. Nature. 2025; 646: 963–72.
    OpenUrlCrossRefPubMed
  80. 80.↵
    2. Tsuchida CA,
    3. Brandes N,
    4. Bueno R,
    5. Trinidad M,
    6. Mazumder T,
    7. Yu B, et al.
    Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells. Cell. 2023; 186: 4567–82.e20.
    OpenUrlCrossRefPubMed
  81. 81.↵
    2. Yang Q,
    3. Abebe JS,
    4. Mai M,
    5. Rudy G,
    6. Kim SY,
    7. Devinsky O,
    8. Long C.
    T4 DNA polymerase prevents deleterious on-target DNA damage and enhances precise CRISPR editing. EMBO J. 2024; 43: 3733–51.
    OpenUrlPubMed
  82. 82.↵
    2. Murray JM,
    3. Carr AM.
    Integrating DNA damage repair with the cell cycle. Curr Opin Cell Biol. 2018; 52: 120–5.
    OpenUrlCrossRefPubMed
  83. 83.↵
    2. Yates LA,
    3. Zhang X,
    4. Burgers PM.
    DNA damage and replication stress checkpoints. Annu Rev Biochem. 2025; 94: 195–221.
    OpenUrlPubMed
  84. 84.↵
    2. Matthews HK,
    3. Bertoli C,
    4. de Bruin RAM.
    Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022; 23: 74–88.
    OpenUrlCrossRefPubMed
  85. 85.↵
    2. Khan GH,
    3. Veltkamp F,
    4. Scheper M,
    5. Hoebe RA,
    6. Claessen N,
    7. Butter L, et al.
    Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response. Eur J Immunol. 2023; 53: e2350562.
  86. 86.↵
    2. Nguyen LN,
    3. Nguyen LNT,
    4. Zhao J,
    5. Schank M,
    6. Dang X,
    7. Cao D, et al.
    Immune activation induces telomeric DNA damage and promotes short-lived effector T cell differentiation in chronic HCV infection. Hepatology. 2021; 74: 2380–94.
    OpenUrlPubMed
  87. 87.↵
    2. Kotliar M,
    3. Cianciolo EE,
    4. Pham DH,
    5. Carroll KR,
    6. Barski A,
    7. Jordan MB, et al.
    Long-term tolerance to islet transplantation via targeted reduction of beta cell-specific T cells. bioRxiv. 2024.
  88. 88.↵
    2. Heylmann D,
    3. Ponath V,
    4. Kindler T,
    5. Kaina B.
    Comparison of DNA repair and radiosensitivity of different blood cell populations. Sci Rep. 2021; 11: 2478.
    OpenUrlCrossRefPubMed
  89. 89.↵
    2. Felgentreff K,
    3. Schuetz C,
    4. Baumann U,
    5. Klemann C,
    6. Viemann D,
    7. Ursu S, et al.
    Differential DNA damage response of peripheral blood lymphocyte populations. Front Immunol. 2021; 12: 739675.
  90. 90.↵
    2. Heylmann D,
    3. Badura J,
    4. Becker H,
    5. Fahrer J,
    6. Kaina B.
    Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: key role of ATM in the differential radiation response. Cell Death Dis. 2018; 9: 1053.
    OpenUrlPubMed
  91. 91.↵
    2. Johnnidis JB,
    3. Muroyama Y,
    4. Ngiow SF,
    5. Chen Z,
    6. Manne S,
    7. Cai Z, et al.
    Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage. Sci Immunol. 2021; 6: eabe3702.
  92. 92.↵
    2. Karl F,
    3. Liang C,
    4. Böttcher-Loschinski R,
    5. Stoll A,
    6. Flamann C,
    7. Richter S, et al.
    Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT. Blood. 2023; 141: 1626–39.
    OpenUrlPubMed
  93. 93.↵
    2. Chen C,
    3. Zheng H,
    4. Horwitz EM,
    5. Ando S,
    6. Araki K,
    7. Zhao P, et al.
    Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity. Sci Adv. 2023; 9: eadf9522.
  94. 94.↵
    2. Callender LA,
    3. Schroth J,
    4. Carroll EC,
    5. Garrod-Ketchley C,
    6. Romano LEL,
    7. Hendy E, et al.
    GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage. Nat Commun. 2021; 12: 3379.
    OpenUrlPubMed
  95. 95.↵
    2. Mix MR,
    3. Harty JT.
    Keeping T cell memories in mind. Trends Immunol. 2022; 43: 1018–31.
    OpenUrlCrossRefPubMed
  96. 96.↵
    2. Liu Q,
    3. Sun Z,
    4. Chen L.
    Memory T cells: strategies for optimizing tumor immunotherapy. Protein Cell. 2020; 11: 549–64.
    OpenUrlCrossRefPubMed
  97. 97.↵
    2. D’Souza AD,
    3. Parish IA,
    4. McKay SE,
    5. Kaech SM,
    6. Shadel GS.
    Aberrant CD8+ T-cell responses and memory differentiation upon viral infection of an ataxia-telangiectasia mouse model driven by hyper-activated Akt and mTORC1 signaling. Am J Pathol. 2011; 178: 2740–51.
    OpenUrlCrossRefPubMed
  98. 98.↵
    2. Gebhardt T,
    3. Park SL,
    4. Parish IA.
    Stem-like exhausted and memory CD8+ T cells in cancer. Nat Rev Cancer. 2023; 23: 780–98.
    OpenUrlCrossRefPubMed
  99. 99.↵
    2. Li W,
    3. Lu L,
    4. Lu J,
    5. Wang X,
    6. Yang C,
    7. Jin J, et al.
    cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy. Sci Transl Med. 2020; 12: eaay9013.
  100. 100.↵
    2. Gulen MF,
    3. Koch U,
    4. Haag SM,
    5. Schuler F,
    6. Apetoh L,
    7. Villunger A, et al.
    Signalling strength determines proapoptotic functions of STING. Nat Commun. 2017; 8: 427.
    OpenUrlCrossRefPubMed
  101. 101.↵
    2. Xian H,
    3. Watari K,
    4. Sanchez-Lopez E,
    5. Offenberger J,
    6. Onyuru J,
    7. Sampath H, et al.
    Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity. 2022; 55: 1370–85.e8.
    OpenUrlCrossRefPubMed
  102. 102.↵
    2. Rivadeneira DB,
    3. Thosar S,
    4. Quann K,
    5. Gunn WG,
    6. Dean VG,
    7. Xie B, et al.
    Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer. Immunity. 2025; 58: 2524–40.e5.
    OpenUrlPubMed
  103. 103.↵
    2. Kelliher JL,
    3. Patra M,
    4. Shuttleworth SL,
    5. Fil D,
    6. Cruse K,
    7. NO Meridia TW, et al.
    236 Manipulating the DNA damage response to combat T cell exhaustion and improve immunotherapy response. J Immunother Cancer. 2025; 13(Suppl 2): A1–A1534.
    OpenUrlAbstract/FREE Full Text
  104. 104.↵
    2. Yates KB,
    3. Tonnerre P,
    4. Martin GE,
    5. Gerdemann U,
    6. Al Abosy R,
    7. Comstock DE, et al.
    Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat Immunol. 2021; 22: 1020–9.
    OpenUrlCrossRefPubMed
  105. 105.↵
    2. Abdel-Hakeem MS,
    3. Manne S,
    4. Beltra JC,
    5. Stelekati E,
    6. Chen Z,
    7. Nzingha K, et al.
    Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol. 2021; 22: 1008–19.
    OpenUrlCrossRefPubMed
  106. 106.↵
    2. Paull TT,
    3. Opresko PL.
    Epigenetic consequences of DNA damage. Mol Cell. 2026; 86: 439–48.
    OpenUrlPubMed
  107. 107.↵
    2. Kakarougkas A,
    3. Ismail A,
    4. Chambers AL,
    5. Riballo E,
    6. Herbert AD,
    7. Künzel J, et al.
    Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol Cell. 2014; 55: 723–32.
    OpenUrlCrossRefPubMed
  108. 108.↵
    2. Kharel A,
    3. Shen J,
    4. Brown R,
    5. Chen Y,
    6. Nguyen C,
    7. Alson D, et al.
    Loss of PBAF promotes expansion and effector differentiation of CD8+ T cells during chronic viral infection and cancer. Cell Rep. 2023; 42: 112649.
  109. 109.↵
    2. Patsoukis N,
    3. Sari D,
    4. Boussiotis VA.
    PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. Cell Cycle. 2012; 11: 4305–9.
    OpenUrlCrossRefPubMed
  110. 110.↵
    2. Lerrer S,
    3. Tocheva AS,
    4. Bukhari S,
    5. Adam K,
    6. Mor A.
    PD-1-stimulated T cell subsets are transcriptionally and functionally distinct. iScience. 2021; 24: 103020.
  111. 111.↵
    2. Yan Q,
    3. Zhang B,
    4. Ling X,
    5. Zhu B,
    6. Mei S,
    7. Yang H, et al.
    CTLA-4 facilitates DNA damage-induced apoptosis by interacting with PP2A. Front Cell Dev Biol. 2022; 10: 728771.
  112. 112.↵
    2. Schumacher B,
    3. Pothof J,
    4. Vijg J,
    5. Hoeijmakers JHJ.
    The central role of DNA damage in the ageing process. Nature. 2021; 592: 695–703.
    OpenUrlCrossRefPubMed
  113. 113.↵
    2. Huang L,
    3. Zhang C,
    4. Jiang A,
    5. Lin A,
    6. Zhu L,
    7. Mou W, et al.
    T-cell senescence in the tumor microenvironment. Cancer Immunol Res. 2025; 13: 618–32.
    OpenUrlPubMed
  114. 114.↵
    2. de Oliveira BSP,
    3. Giovinazzo A,
    4. Putti S,
    5. Merolle M,
    6. Orsini T,
    7. Tocchini-Valentini GD, et al.
    Hematopoietic stem/progenitor cell transplantation recovers immune defects and prevents lymphomas in Atm-deficient mice. Exp Hematol Oncol. 2024; 13: 81.
    OpenUrlPubMed
  115. 115.↵
    2. Lanna A,
    3. Gomes DC,
    4. Muller-Durovic B,
    5. McDonnell T,
    6. Escors D,
    7. Gilroy DW, et al.
    A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol. 2017; 18: 354–63.
    OpenUrlPubMed
  116. 116.↵
    2. Rossiello F,
    3. Jurk D,
    4. Passos JF,
    5. d’Adda di Fagagna F.
    Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol. 2022; 24: 135–47.
    OpenUrlCrossRefPubMed
  117. 117.↵
    2. Lanna A,
    3. Henson SM,
    4. Escors D,
    5. Akbar AN.
    The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014; 15: 965–72.
    OpenUrlCrossRefPubMed
  118. 118.↵
    2. Kasakovski D,
    3. Xu L,
    4. Li Y.
    T cell senescence and CAR-T cell exhaustion in hematological malignancies. J Hematol Oncol. 2018; 11: 91.
    OpenUrlCrossRefPubMed
  119. 119.↵
    2. González-Osuna L,
    3. Sierra-Cristancho A,
    4. Rojas C,
    5. Cafferata EA,
    6. Melgar-Rodríguez S,
    7. Cárdenas AM, et al.
    Premature senescence of T-cells favors bone loss during osteolytic diseases. A new concern in the osteoimmunology arena. Aging Dis. 2021; 12: 1150–61.
    OpenUrlPubMed
  120. 120.↵
    2. Liu X,
    3. Hoft DF,
    4. Peng G.
    Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy. J Clin Invest. 2020; 130: 1073–83.
    OpenUrlCrossRefPubMed
  121. 121.↵
    2. Ye J,
    3. Peng G.
    Controlling T cell senescence in the tumor microenvironment for tumor immunotherapy. Oncoimmunology. 2015; 4: e994398.
  122. 122.↵
    2. Giralt S,
    3. Bishop MR.
    Principles and overview of allogeneic hematopoietic stem cell transplantation. Cancer Treat Res. 2009; 144: 1–21.
    OpenUrlCrossRefPubMed
  123. 123.↵
    2. Omari Shekaftik S,
    3. Nasirzadeh N.
    8-Hydroxy-2′-deoxyguanosine (8-OHdG) as a biomarker of oxidative DNA damage induced by occupational exposure to nanomaterials: a systematic review. Nanotoxicology. 2021; 15: 850–64.
    OpenUrlPubMed
  124. 124.↵
    2. Zhao J,
    3. Wei C,
    4. Wang S,
    5. Zhang Y,
    6. Wang W,
    7. Zhao D, et al.
    The intrinsic defects of T cells impact the efficacy of CAR-T therapy in patients with diffuse large B-cell lymphoma. Blood Cancer J. 2023; 13: 186.
    OpenUrlPubMed
  125. 125.↵
    2. Chung AW,
    3. Anand K,
    4. Anselme AC,
    5. Chan AA,
    6. Gupta N,
    7. Venta LA, et al.
    A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer. Sci Transl Med. 2021; 13: eabj5070.
  126. 126.↵
    2. Bahar ME,
    3. Kim HJ,
    4. Kim DR.
    Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. 2023; 8: 455.
    OpenUrlPubMed
  127. 127.↵
    2. Liu Y,
    3. Su Z,
    4. Tavana O,
    5. Gu W.
    Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell. 2024; 42: 946–67.
    OpenUrlCrossRefPubMed
  128. 128.↵
    2. Fielden J,
    3. Siegner SM,
    4. Gallagher DN,
    5. Schröder MS,
    6. Dello Stritto MR,
    7. Lam S, et al.
    Comprehensive interrogation of synthetic lethality in the DNA damage response. Nature. 2025; 640: 1093–102.
    OpenUrlCrossRefPubMed
  129. 129.↵
    2. Peripolli S,
    3. Meneguello L,
    4. Perrod C,
    5. Singh T,
    6. Patel H,
    7. Rahman ST, et al.
    Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner. Nat Commun. 2024; 15: 1579.
    OpenUrlCrossRefPubMed
  130. 130.↵
    2. Gaillard H,
    3. García-Muse T,
    4. Aguilera A.
    Replication stress and cancer. Nat Rev Cancer. 2015; 15: 276–89.
    OpenUrlCrossRefPubMed
  131. 131.↵
    2. Jiao X,
    3. Liu J,
    4. Wu Y,
    5. Zhong Q,
    6. Zhu L,
    7. Wang L, et al.
    Sequential treatment with PARPi and WEE1i enhances antitumor immune responses in preclinical models of ovarian cancer. Sci Transl Med. 2025; 17: eadu6989.
  132. 132.↵
    2. Yap TA,
    3. Ngoi N,
    4. Dumbrava EE,
    5. Karp DD,
    6. Rodon Ahnert J,
    7. Fu S, et al.
    NCI10329: phase Ib sequential trial of agents against DNA repair (STAR) study to investigate the sequential combination of the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib (ola) and WEE1 inhibitor (WEE1i) adavosertib (ada) in patients (pts) with DNA damage response (DDR)-aberrant advanced tumors, enriched for BRCA1/2 mutated and CCNE1 amplified cancers. Eur J Cancer. 2022; 174: S7.
    OpenUrl
  133. 133.↵
    2. Dillon MT,
    3. Guevara J,
    4. Mohammed K,
    5. Patin EC,
    6. Smith SA,
    7. Dean E, et al.
    Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. J Clin Invest. 2024; 134: e175369.
  134. 134.↵
    2. Friedlander M,
    3. Lee YC,
    4. Tew WP.
    Managing adverse effects associated with poly (ADP-ribose) polymerase inhibitors in ovarian cancer: a synthesis of clinical trial and real-world data. Am Soc Clin Oncol Educ Book. 2023; 43: e390876.
  135. 135.↵
    2. Chen L,
    3. Zou Y,
    4. Sun R,
    5. Huang M,
    6. Zhu X,
    7. Tang X, et al.
    Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader. Cell Death Dis. 2024; 15: 898.
    OpenUrlPubMed
  136. 136.↵
    2. An J,
    3. Zhang CP,
    4. Qiu HY,
    5. Zhang HX,
    6. Chen QB,
    7. Zhang YM, et al.
    Enhancement of the viability of T cells electroporated with DNA via osmotic dampening of the DNA-sensing cGAS-STING pathway. Nat Biomed Eng. 2024; 8: 149–64.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Email Article
Citation Tools

Jump to section

Keywords