bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒04‒25
twenty-two papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. EMBO J. 2021 Apr 20. e108164
      Cellular senescence is considered to be a major driver of aging, yet the mechanisms explaining the accumulation of senescent cells during life time remain unclear. In this issue, Lagnado et al (2021) show that neutrophils can trigger the senescence of neighboring cells by transmitting reactive oxygen species (ROS), which they normally produce to fight pathogens. The main genomic targets of the neutrophil-mediated ROS damage are telomeres, supporting an intimate interplay between telomere homeostasis and oxidative stress in senescence and consequently aging.
  2. Nat Commun. 2021 Apr 20. 12(1): 2345
      Age is the most important risk factor for cancer, as cancer incidence and mortality increase with age. However, how molecular alterations in tumours differ among patients of different age remains largely unexplored. Here, using data from The Cancer Genome Atlas, we comprehensively characterise genomic, transcriptomic and epigenetic alterations in relation to patients' age across cancer types. We show that tumours from older patients present an overall increase in genomic instability, somatic copy-number alterations (SCNAs) and somatic mutations. Age-associated SCNAs and mutations are identified in several cancer-driver genes across different cancer types. The largest age-related genomic differences are found in gliomas and endometrial cancer. We identify age-related global transcriptomic changes and demonstrate that these genes are in part regulated by age-associated DNA methylation changes. This study provides a comprehensive, multi-omics view of age-associated alterations in cancer and underscores age as an important factor to consider in cancer research and clinical practice.
  3. Geroscience. 2021 Apr 24.
      Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab')2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-γ and tumor necrosis factor-α are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-γ. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.
    Keywords:  Adipose tissue; Glucose intolerance; Liver; Macrophages; Skeletal muscle; T lymphocyte
  4. Cell Cycle. 2021 Apr 05. 1-13
      Tau accumulation is a core component of Alzheimer's disease and other neurodegenerative tauopathies. While tau's impact on neurons is a major area of research, the effect of extracellular tau on astrocytes is largely unknown. This article summarizes our recent studies showing that astrocyte senescence plays a critical role in neurodegenerative diseases and integrates extracellular tau into the regulatory loop of senescent astrocyte-mediated neurotoxicity. Human astrocytes in vitro undergoing senescence were shown to acquire the inflammatory senescence-associated secretory phenotype (SASP) and toxicity to neurons, which may recapitulate aging- and disease-associated neurodegeneration. Here, we show that human astrocytes exposed to extracellular tau in vitro also undergo cellular senescence and acquire a neurotoxic SASP (e.g. IL-6 secretion), with oxidative stress response (indicated by upregulated NRF2 target genes) and a possible activation of inflammasome (indicated by upregulated ASC and IL-1β). These findings suggest that senescent astrocytes induced by various conditions and insults, including tau exposure, may represent a therapeutic target to inhibit or delay the progression of neurodegenerative diseases. We also discuss the pathological activity of extracellular tau in microglia and astrocytes, the disease relevance and diversity of tau forms, therapeutics targeting senescence in neurodegeneration, and the roles of p53 and its isoforms in astrocyte-mediated neurotoxicity and neuroprotection.
    Keywords:  Alzheimer’s disease; SASP; astrocyte senescence; neurodegeneration; p53 isoforms; tau
  5. Dev Cell. 2021 Apr 16. pii: S1534-5807(21)00309-9. [Epub ahead of print]
      Lipids play crucial roles in regulating aging and longevity. In the past few decades, a series of genetic pathways have been discovered to regulate lifespan in model organisms. Interestingly, many of these regulatory pathways are linked to lipid metabolism and lipid signaling. Lipid metabolic enzymes undergo significant changes during aging and are regulated by different longevity pathways. Lipids also actively modulate lifespan and health span as signaling molecules. In this review, we summarize recent insights into the roles of lipid metabolism and lipid signaling in aging and discuss lipid-related interventions in promoting longevity.
    Keywords:  aging; lipid metabolism; lipid signals; longevity
  6. Mech Ageing Dev. 2021 Apr 01. pii: S0047-6374(21)00050-6. [Epub ahead of print]196 111478
      Pigment epithelium-derived factor (PEDF) is an endogenously produced protein that contributes to cell growth arrest, and reduced levels of PEDF are associated with the progression of cellular senescence and the aging process. However, the mechanisms underlying PEDF regulation of these events are not completely clear. Increased PEDF activity may induce anti-aging processes, suggesting the potential therapeutic value of PEDF as an anti-aging and age-related disease. In this review, we recapitulate the molecular and cellular mechanisms of aging following the characteristics and specific roles of the PEDF in cell cycle arrest and its relevance to cellular senescence and aging pathways. In this context, the discovery and fluctuations of PEDF in age-related diseases are summarised. In light of the importance of PEDF in cellular senescence and aging processes, better comprehension of the mechanism(s) of PEDF in the regulation of cell cycle and the aging process can conceivably facilitate the development of therapeutic strategies for diseases that occur with aging.
    Keywords:  Age-related diseases; Aging; Cell cycle; Cellular senescence; Pigment epithelium-derived factor
  7. JBMR Plus. 2021 Apr;5(4): e10488
      Changes in aging bone that lead to osteoporosis are mediated at multiple levels, including hormonal alterations, skeletal unloading, and accumulation of senescent cells. This pathological interplay is superimposed upon medical conditions, potentially bone-wasting medications, modifiable and unmodifiable personal risk factors, and genetic predisposition that accelerate bone loss with aging. In this study, the focus is on bone hemostasis and its dysregulation with aging. The major physiological changes with aging in bone and the role of cellular senescence in contributing to age-related osteoporosis are summarized. The aspects of bone aging are reviewed including remodeling deficits, uncoupling phenomena, inducers of cellular senescence related to bone aging, roles of the senescence-associated secretory phenotype, radiation-induced bone loss as a model for bone aging, and the accumulation of senescent cells in the bone microenvironment as a predominant mechanism for age-related osteoporosis. The study also addresses the rationale and potential for therapeutic interventions based on the clearance of senescent cells or suppression of the senescence-associated secretory phenotype. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
  8. Porto Biomed J. 2021 Jan-Feb;6(1):6(1): e120
      Ageing is a risk factor for chronic diseases including cancer, cardiovascular diseases, neurodegenerative disorders, and metabolic syndrome. Among others, senescence mechanisms have become a target of huge research on the topic of the ageing process. Cellular senescence is a state of an irreversible growth arrest that occurs in response to various forms of cellular stress and is characterized by a pro-inflammatory secretory phenotype. Multiple studies showed that cellular senescence occurs in both physiological and pathophysiological conditions. Senescent cells accumulate with ageing and can contribute to age-related decline in tissue function. Obesity is a metabolic condition that can accelerate the ageing process by promoting a premature induction of the senescent state of the cells. In contrast, caloric restriction without malnutrition is currently the most effective non-genetic intervention to delay ageing, and its potential in decreasing the cellular senescent burden is suggested. Here, it will be highlighted the cellular and molecular mechanisms involved in cellular senescence and discussed some of the research that is being done about how environmental conditions such as diet can affect the accumulation of senescent cells.
    Keywords:  ageing; caloric restriction; caloric restriction mimetics; cellular senescence; obesity
  9. Aging (Albany NY). 2021 Apr 22. 13
      Dysfunction of bone marrow mesenchymal stem cells (BMSCs), osteoblasts and osteocytes may be one of the main causes of bone loss in the elderly. In the present study, we found osteogenic cells from aged rats all exhibited senescence changes, with the most pronounced senescence changes in osteocytes. Meanwhile, the proliferative capacity and functional activity of osteogenic cells from aged rats were suppressed. Osteogenic differentiation capacity of BMSCs from aged rats decreased while adipogenic capacity increased. The mineralization capacity, ALP activity and osteogenic proteins expression of osteoblasts from aged rats decreased. Additionally, osteocytes from aged rats up-expressed sclerosteosis protein, a negative regulator of bone formation. To inhibit osteogenic cell senescence, we use low magnitude vibration (LMV) to eliminate the senescent osteogenic cells. After LMV treatment, the number of osteogenic cells staining positively for senescence-associated-β-galactosidase (SA-β-Gal) decreased significantly. Besides, the expression of anti-aging protein SIRT1 was upregulated significantly, while p53 and p21 were downregulated significantly after LMV treatment. Thus, the LMV can inhibit the senescence of osteogenic cells partly through the Sirt1/p53/p21 axis. Furthermore, LMV was found to promote bone formation of aged rats. These results suggest that the inhibition of osteogenic cell senescence by LMV is a valuable treatment to prevent or delay osteoporosis.
    Keywords:  low magnitude vibration; osteogenesis; osteoporosis; senescence
  10. Elife. 2021 Apr 20. pii: e62952. [Epub ahead of print]10
      Aging is associated with distinct phenotypical, physiological, and functional changes, leading to disease and death. The progression of aging-related traits varies widely among individuals, influenced by their environment, lifestyle, and genetics. In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and towards redox-related pathways, mainly in liver and heart. Collectively, the data provide a framework to further understand and characterize processes of aging at the individual organism and organ levels.
    Keywords:  computational biology; mouse; systems biology
  11. J Cereb Blood Flow Metab. 2021 Apr 04. 271678X211006291
      Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme for the synthesis of nicotinamide adenine dinucleotide (NAD) in the salvaging pathway. Though NAMPT inhibitors such as FK866 were originally developed as anti-cancer drugs, they also display neuroprotective effects. Here we show that the administration of FK866 at 0.5 mg/kg (ip, qod) for four weeks, i.e., ∼1% of the dose used for the treatment of cancer, significantly alleviates the aging-induced impairment of cognition and locomotor activity. Mechanistically, FK866 enhanced autophagy, reduced protein aggregation, and inhibited neuroinflammation indicated by decreasing TNFα, IL-6, GFAP, and Iba1 levels in the aged mouse brain. Though FK866 did not affect the total NAD and nicotinamide mononucleotide (NMN) levels in the mouse brain at the dose we used, FK866 increased nicotinamide (NAM) level in the young mouse brain and decreased NAM level in the aged mouse brain. On the other hand, FK866 did not affect the serum glucose, cholesterol, and triglyceride of young and aged mice and exhibited no effects on the various indices of young mice. Thus, the NAMPT inhibitor can be repurpose to counteract the cognitive impairment upon aging. We also envision that NAMPT inhibitor can be used for the treatment of age-related neurodegenerative diseases.
    Keywords:  Aging; FK866; cognitive impairment; nicotinamide phosphoribosyltransferase; protein aggregation
  12. Elife. 2021 Apr 20. pii: e61138. [Epub ahead of print]10
      Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'order' and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.
    Keywords:  computational biology; mouse; regenerative medicine; stem cells; systems biology
  13. Redox Biol. 2021 Apr 01. pii: S2213-2317(21)00111-7. [Epub ahead of print]43 101963
      Senescence of bone marrow-derived mesenchymal stem cells (BMSCs) has been widely reported to be closely correlated with aging-related diseases, including osteoporosis (OP). Moreover, the beneficial functions of BMSCs decline with age, limiting their therapeutic efficacy in OP. In the present study, using RNA sequencing (RNA-Seq), we found that leucine-rich repeat containing 17 (LRRc17) expression in BMSCs was highly positively correlated with age. Therefore, we investigated whether LRRc17 knockdown could rejuvenate aged MSCs and increase their therapeutic efficacy in OP. Consistent with the RNA-Seq results, the protein expression of LRRc17 in senescent BMSCs was significantly increased, whereas LRRc17 knockdown inhibited cell apoptosis and reduced the expression of age-related proteins and G2 and S phase quiescence. Furthermore, LRRc17 knockdown shifted BMSCs from adipogenic to osteogenic differentiation, indicating the critical role of LRRc17 in BMSC senescence and differentiation. Additionally, similar to rapamycin (RAPA) treatment, LRRc17 knockdown activated mitophagy via inhibition of the mTOR/PI3K pathway, which consequently reduced mitochondrial dysfunction and inhibited BMSC senescence. However, the effects of LRRc17 knockdown were significantly blocked by the autophagy inhibitor hydroxychloroquine (HCQ), demonstrating that LRRc17 knockdown prevented BMSC senescence by activating mitophagy. In vivo, compared with untransfected aged mouse-derived BMSCs (O-BMSCs), O-BMSCs transfected with sh-LRRc17 showed effective amelioration of ovariectomy (OVX)-induced bone loss. Collectively, these results indicated that LRRc17 knockdown rejuvenated senescent BMSCs and thus enhanced their therapeutic efficacy in OP by activating autophagy.
    Keywords:  Aging; BMSCs; LRRc17; Mitophagy; Osteoporosis
  14. Genes Immun. 2021 Apr 19.
      The microbiome plays a fundamental role in the maturation, function, and regulation of the host-immune system from birth to old age. In return, the immune system has co-evolved a mutualistic relationship with trillions of beneficial microbes residing our bodies while mounting efficient responses to fight invading pathogens. As we age, both the immune system and the gut microbiome undergo significant changes in composition and function that correlate with increased susceptibility to infectious diseases and reduced vaccination responses. Emerging studies suggest that targeting age-related dysbiosis can improve health- and lifespan, in part through reducing systemic low-grade inflammation and immunosenescence-two hallmarks of the aging process. However-a cause and effect relationship of age-related dysbiosis and associated functional declines in immune cell functioning have yet to be demonstrated in clinical settings. This review aims to (i) give an overview on hallmarks of the aging immune system and gut microbiome, (ii) discuss the impact of age-related changes in the gut commensal community structure (introduced as microb-aging) on host-immune fitness and health, and (iii) summarize prebiotic- and probiotic clinical intervention trials aiming to reinforce age-related declines in immune cell functioning through microbiome modulation or rejuvenation.
  15. Exp Dermatol. 2021 Apr 23.
      Emerging evidence has pointed to the noxious effects of senescent cells in various tissues, and senescent cells in the epidermis are known to accumulate with age. We hypothesized that there is a mechanism by which senescent cells in the epidermis are preferentially removed and that the function of such removal mechanism declines as age increases. In this study, we investigated whether Notch signaling is involved in such senescent cell removal. We found that Notch1 receptor was expressed more highly in p16INK4a -positive senescent cells than in surrounding cells in human epidermis both in young and old subjects. On the other hand, the expression of its ligand JAG1 was decreased in the epidermis of aged subjects. When normal epidermal cells and UVB-irradiated senescent cells were mixed and three-dimensional reconstructed epidermis was developed in vitro, the senescent cells were preferentially removed from the basal layer and located in the upper layer. We also found that the depletion of senescent cells from the basal layer was suppressed by JAG1 knockdown in normal cells or using a Notch signaling inhibitor. From these results, Notch signaling may be involved in senescent cell removal in the epidermis and the age-related decrease of JAG1 expression in the basal layer may lead to accumulation of senescent cells owing to reduced activation of Notch signaling.
    Keywords:  3D reconstructed epidermis; Notch signaling; cell competition; cellular senescence; epidermis
  16. Aging (Albany NY). 2021 Apr 20. 13
      Mounting evidence suggests that mitochondrial dysfunction and impaired mitophagy lead to Parkinson's disease (PD). Quercetin, one of the most abundant polyphenolic flavonoids, displays many health-promoting biological effects in many diseases. We explored the neuroprotective effect of quercetin in vivo in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and in vitro in 6-OHDA-treated PC12 cells. In vitro, we found that quercetin (20 μM) treatment improved mitochondrial quality control, reduced oxidative stress, increased the levels of the mitophagy markers PINK1 and Parkin and decreased α-synuclein protein expression in 6-OHDA-treated PC12 cells. Moreover, our in vivo findings demonstrated that administration of quercetin also relieved 6-OHDA-induced progressive PD-like motor behaviors, mitigated neuronal death and reduced mitochondrial damage and α-synuclein accumulation in PD rats. Furthermore, the neuroprotective effect of quercetin was suppressed by knockdown of either Pink1 or Parkin.
    Keywords:  Parkinson's disease; mitochondria quality control; mitophagy; quercetin
  17. Aging (Albany NY). 2021 Apr 22. 13
      Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β superfamily of cytokines, is a critical rejuvenation factor in aging cells. GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.
    Keywords:  GDF11; age-related diseases; aging; growth differentiation factor 11; regeneration; transforming growth factor
  18. Mol Biol Evol. 2021 Apr 19. pii: msab112. [Epub ahead of print]
      Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. While many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are significant as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and non-tumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally we integrated our data to study interspecies DNA methylation levels at orthologous CpG sites. Globally, we found considerable differences between the characteristics of DNA methylation alterations in cancer and aging in both species. Moreover, we describe robust evidence for the conservation of the specific cancer and aging epigenomic signatures in human and mouse. Our observations point towards the preservation of the functional consequences of these alterations at multiple levels of genomic regulation. Finally, our analyses reveal a role for the genomic context in explaining disease- and species-specific epigenetic traits.
  19. Science. 2021 Apr 22. pii: eabd5491. [Epub ahead of print]
      The coenzyme nicotinamide adenine dinucleotide phosphate (NADP+) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of NADK2 in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.
  20. Commun Biol. 2021 Apr 22. 4(1): 497
      Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8+ T cells, and generated systemic anti-tumor immunity to the tumor. ExoSTING at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. ExoSTING is a novel, differentiated therapeutic candidate that leverages the natural biology of EVs to enhance the activity of CDNs.
  21. Nat Commun. 2021 Apr 22. 12(1): 2388
      To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-κB pathway in human adipose tissue. The circadian clock function is impaired in omental fat from obese patients. ChIP-seq analyses reveal that the core clock activator, BMAL1 binds to several thousand target genes. NF-κB competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-κB consensus motifs. Obesity relocalizes BMAL1 occupancy genome-wide in human omental fat, thereby altering the transcription of numerous target genes involved in metabolic inflammation and adipose tissue remodeling. Eventually, clock dysfunction appears at early stages of obesity in mice and is corrected, together with impaired metabolism, by NF-κB inhibition. Collectively, our results reveal a relationship between NF-κB and the molecular clock in adipose tissue, which may contribute to obesity-related complications.
  22. Front Immunol. 2021 ;12 660184
      Mutations in the TREX1 3' → 5' exonuclease are associated with a spectrum of autoimmune disease phenotypes in humans and mice. Failure to degrade DNA activates the cGAS-STING DNA-sensing pathway signaling a type-I interferon (IFN) response that ultimately drives immune system activation. TREX1 and the cGAS-STING DNA-sensing pathway have also been implicated in the tumor microenvironment, where TREX1 is proposed to degrade tumor-derived DNA that would otherwise activate cGAS-STING. If tumor-derived DNA were not degraded, the cGAS-STING pathway would be activated to promote IFN-dependent antitumor immunity. Thus, we hypothesize TREX1 exonuclease inhibition as a novel immunotherapeutic strategy. We present data demonstrating antitumor immunity in the TREX1 D18N mouse model and discuss theory surrounding the best strategy for TREX1 inhibition. Potential complications of TREX1 inhibition as a therapeutic strategy are also discussed.
    Keywords:  cancer; exonuclease; immunotherapy; inhibition; small-molecule