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Abstract

Cellular senescence is a tumor-suppressive program that promotes tissue homeostasis by identifying damaged cells for immune-mediated clearance. Thus, the ability to evade senescence and the ensuing immune surveillance is a hallmark of cancer. Reactivation of senescence programs can result in profound immune-mediated tumor regressions or sensitize tumors to immunotherapy, although the aberrant persistence of senescent cells can promote tissue decline and contribute to the side effects of some cancer therapies. In this review, we first briefly describe the discovery of senescence as a tumor-suppressive program. Next, we highlight the dueling good and bad effects of the senescence-associated secretory program (SASP) in cancer, including SASP-dependent immune effects. We then summarize the beneficial and deleterious effects of senescence induction by cancer therapies and strategies in development to leverage senescence therapeutically. Finally, we highlight challenges and unmet needs in understanding senescence in cancer and developing senescence-modulating therapies.

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2023-04-11
2024-04-22
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Literature Cited

  1. Aarts M, Georgilis A, Beniazza M, Beolchi P, Banito A et al. 2017. Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence. Genes Dev 31:2085–98
    [Google Scholar]
  2. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P et al. 2013. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15:978–90
    [Google Scholar]
  3. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A et al. 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–18
    [Google Scholar]
  4. Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A et al. 2010. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Investig. 120:681–93
    [Google Scholar]
  5. Amor C, Feucht J, Leibold J, Ho YJ, Zhu C et al. 2020. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583:127–32
    [Google Scholar]
  6. Aoshiba K, Tsuji T, Nagai A. 2003. Bleomycin induces cellular senescence in alveolar epithelial cells. Eur. Respir. J. 22:436–43
    [Google Scholar]
  7. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ et al. 2016. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530:184–89Revealed that senescent cell clearance delays tumorigenesis and extends lifespan during normal aging.
    [Google Scholar]
  8. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG et al. 2011. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–36Showed that ablation of senescent cells ameliorates age-related dysfunction and established the field of senolytics.
    [Google Scholar]
  9. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D et al. 2006. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:633–37
    [Google Scholar]
  10. Basisty N, Kale A, Jeon OH, Kuehnemann C, Payne T et al. 2020. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLOS Biol 18:e3000599
    [Google Scholar]
  11. Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV et al. 2009. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging 1:402–11
    [Google Scholar]
  12. Bhisitkul R, Klier S, Tsuruda P, Xie B, Masaki L et al. 2022. UBX1325, a novel senolytic treatment for patients with advanced DME or wet AMD: 24-week results of a phase 1 study. Investig. Ophthalmol. Vis. Sci. 63:4287 Abstr.)
    [Google Scholar]
  13. Bilusic M, Heery CR, Collins JM, Donahue RN, Palena C et al. 2019. Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J. Immunother. Cancer 7:240
    [Google Scholar]
  14. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH et al. 2005. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–65
    [Google Scholar]
  15. Calls A, Torres-Espin A, Navarro X, Yuste VJ, Udina E, Bruna J 2021. Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response. Neuro-Oncology 23:88–99
    [Google Scholar]
  16. Campisi J, d'Adda di Fagagna F. 2007. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8:729–40
    [Google Scholar]
  17. Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A et al. 1999. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 59:3761–67
    [Google Scholar]
  18. Chang J, Wang Y, Shao L, Laberge RM, Demaria M et al. 2016. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22:78–83
    [Google Scholar]
  19. Chen H-A, Ho Y-J, Mezzadra R, Adrover JM, Smolkin R et al. 2022. Senescence rewires microenvironment sensing to facilitate anti-tumor immunity. Cancer Discov https://doi.org/10.1158/2159-8290.CD-22-0528
    [Google Scholar]
  20. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA et al. 2005. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–30
    [Google Scholar]
  21. Chibaya L, Snyder J, Ruscetti M. 2022. Senescence and the tumor-immune landscape: implications for cancer immunotherapy. Semin. Cancer Biol. 86:827–45
    [Google Scholar]
  22. Chicas A, Kapoor A, Wang X, Aksoy O, Evertts AG et al. 2012. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. PNAS 109:8971–76
    [Google Scholar]
  23. Chicas A, Wang X, Zhang C, McCurrach M, Zhao Z et al. 2010. Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17:376–87
    [Google Scholar]
  24. Chien Y, Scuoppo C, Wang X, Fang X, Balgley B et al. 2011. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–36
    [Google Scholar]
  25. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ et al. 2005. Tumour biology: senescence in premalignant tumours. Nature 436:642
    [Google Scholar]
  26. Coppe JP, Desprez PY, Krtolica A, Campisi J. 2010. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. Mech. Dis. 5:99–118
    [Google Scholar]
  27. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP et al. 2008. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLOS Biol 6:2853–68
    [Google Scholar]
  28. Dabritz JH, Yu Y, Milanovic M, Schonlein M, Rosenfeldt MT et al. 2016. CD20-targeting immunotherapy promotes cellular senescence in B-cell lymphoma. Mol. Cancer Ther. 15:1074–81
    [Google Scholar]
  29. De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ et al. 2019. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566:73–78
    [Google Scholar]
  30. Demaria M, O'Leary MN, Chang J, Shao L, Liu S et al. 2017. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov 7:165–76Evidence that senolytics mitigate doxorubicin morbidity, tumor relapse, and metastasis to improve survival.
    [Google Scholar]
  31. Desdin-Mico G, Soto-Heredero G, Aranda JF, Oller J, Carrasco E et al. 2020. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368:1371–76
    [Google Scholar]
  32. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P et al. 2006. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–42
    [Google Scholar]
  33. Di Micco R, Sulli G, Dobreva M, Liontos M, Botrugno OA et al. 2011. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat. Cell Biol. 13:292–302
    [Google Scholar]
  34. Dolgin E. 2020. Send in the senolytics. Nat. Biotechnol. 38:1371–77
    [Google Scholar]
  35. Dominguez C, McCampbell KK, David JM, Palena C. 2017. Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer. JCI Insight 2:e94296
    [Google Scholar]
  36. Dorr JR, Yu Y, Milanovic M, Beuster G, Zasada C et al. 2013. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501:421–25
    [Google Scholar]
  37. Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P et al. 2017. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402–6
    [Google Scholar]
  38. Eggert T, Wolter K, Ji J, Ma C, Yevsa T et al. 2016. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30:533–47
    [Google Scholar]
  39. Fletcher-Sananikone E, Kanji S, Tomimatsu N, Di Cristofaro LFM, Kollipara RK et al. 2021. Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence. Cancer Res 81:5935–47
    [Google Scholar]
  40. Fleury H, Malaquin N, Tu V, Gilbert S, Martinez A et al. 2019. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat. Commun. 10:2556
    [Google Scholar]
  41. Freund A, Patil CK, Campisi J. 2011. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 30:1536–48
    [Google Scholar]
  42. Fung AS, Wu L, Tannock IF. 2009. Concurrent and sequential administration of chemotherapy and the Mammalian target of rapamycin inhibitor temsirolimus in human cancer cells and xenografts. Clin. Cancer Res. 15:5389–95
    [Google Scholar]
  43. Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E et al. 2020. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non–small-cell lung cancer. J. Clin. Oncol. 38:1505–17
    [Google Scholar]
  44. Galiana I, Lozano-Torres B, Sancho M, Alfonso M, Bernardos A et al. 2020. Preclinical antitumor efficacy of senescence-inducing chemotherapy combined with a nanoSenolytic. J. Control Release 323:624–34
    [Google Scholar]
  45. González-Gualda E, Pàez-Ribes M, Lozano-Torres B, Macias D, Wilson JR III et al. 2020. Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 19:e13142
    [Google Scholar]
  46. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O et al. 2019. Cellular senescence: defining a path forward. Cell 179:813–27
    [Google Scholar]
  47. Goy E, Tomezak M, Facchin C, Martin N, Bouchaert E et al. 2022. The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion. eLife 11:e67190
    [Google Scholar]
  48. Grimm J, Hufnagel A, Wobser M, Borst A, Haferkamp S et al. 2018. BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1. Oncogenesis 7:71
    [Google Scholar]
  49. Guerrero A, Guiho R, Herranz N, Uren A, Withers DJ et al. 2020. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 19:e13133
    [Google Scholar]
  50. Guerrero A, Herranz N, Sun B, Wagner V, Gallage S et al. 2019. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1:1074–88
    [Google Scholar]
  51. Guo S, Diep D, Plongthongkum N, Fung HL, Zhang K, Zhang K. 2017. Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA. Nat. Genet. 49:635–42
    [Google Scholar]
  52. Gutzmer R, Stroyakovskiy D, Gogas H, Robert C, Lewis K et al. 2020. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395:1835–44
    [Google Scholar]
  53. Haferkamp S, Borst A, Adam C, Becker TM, Motschenbacher S et al. 2013. Vemurafenib induces senescence features in melanoma cells. J. Investig. Dermatol. 133:1601–9
    [Google Scholar]
  54. Halazonetis TD, Gorgoulis VG, Bartek J. 2008. An oncogene-induced DNA damage model for cancer development. Science 319:1352–55
    [Google Scholar]
  55. Hao X, Zhao B, Zhou W, Liu H, Fukumoto T et al. 2021. Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype. iScience 24:102016
    [Google Scholar]
  56. Hayes TK, Neel NF, Hu C, Gautam P, Chenard M et al. 2016. Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell 29:75–89
    [Google Scholar]
  57. Hayflick L, Moorhead PS. 1961. The serial cultivation of human diploid cell strains. Exp. Cell. Res. 25:585–621Discovery of senescence as cell cycle arrest resulting from the finite proliferative capacity of human fibroblasts.
    [Google Scholar]
  58. He Y, Zhang X, Chang J, Kim HN, Zhang P et al. 2020. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat. Commun. 11:1996
    [Google Scholar]
  59. Hernandez-Segura A, Nehme J, Demaria M. 2018. Hallmarks of cellular senescence. Trends Cell Biol 28:436–53
    [Google Scholar]
  60. Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N et al. 2019. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. eBioMedicine 47:446–56
    [Google Scholar]
  61. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. 2013. Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–59
    [Google Scholar]
  62. Iannello A, Thompson TW, Ardolino M, Lowe SW, Raulet DH. 2013. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210:2057–69
    [Google Scholar]
  63. Iske J, Seyda M, Heinbokel T, Maenosono R, Minami K et al. 2020. Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nat. Commun. 11:4289
    [Google Scholar]
  64. Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ et al. 2018. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175:984–97.e24
    [Google Scholar]
  65. Jochems F, Thijssen B, De Conti G, Jansen R, Pogacar Z et al. 2021. The Cancer SENESCopedia: a delineation of cancer cell senescence. Cell Rep 36:109441
    [Google Scholar]
  66. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R et al. 2019. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. eBioMedicine 40:554–63
    [Google Scholar]
  67. Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R et al. 2014. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother. Pharmacol. 74:593–602
    [Google Scholar]
  68. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T et al. 2011. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–51
    [Google Scholar]
  69. Kansara M, Leong HS, Lin DM, Popkiss S, Pang P et al. 2013. Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. J. Clin. Investig. 123:5351–60
    [Google Scholar]
  70. Kemp A. 2022. Update on CALLA phase III trial of concurrent use of Imfinzi and chemoradiotherapy in locally advanced cervical cancer News Release AstraZeneca: Mar. 24
  71. Khan S, Zhang X, Lv D, Zhang Q, He Y et al. 2019. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25:1938–47
    [Google Scholar]
  72. Kirkland JL, Tchkonia T. 2020. Senolytic drugs: from discovery to translation. J. Intern. Med. 288:518–36
    [Google Scholar]
  73. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J 2001. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. PNAS 98:12072–77First indication that the SASP can promote tumor progression.
    [Google Scholar]
  74. Kusumoto D, Seki T, Sawada H, Kunitomi A, Katsuki T et al. 2021. Anti-senescent drug screening by deep learning-based morphology senescence scoring. Nat. Commun. 12:257
    [Google Scholar]
  75. Kusunoki Y, Yamaoka M, Kubo Y, Hayashi T, Kasagi F et al. 2010. T-cell immunosenescence and inflammatory response in atomic bomb survivors. Radiat. Res. 174:870–76
    [Google Scholar]
  76. Lasry A, Ben-Neriah Y. 2015. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol 36:217–28
    [Google Scholar]
  77. Lee CS, Baek J, Han SY. 2017. The role of kinase modulators in cellular senescence for use in cancer treatment. Molecules 22:1411
    [Google Scholar]
  78. Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M et al. 2021. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 22:450–62
    [Google Scholar]
  79. Lex K, Maia Gil M, Lopes-Bastos B, Figueira M, Marzullo M et al. 2020. Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish. PNAS 117:15066–74
    [Google Scholar]
  80. Li Y, Nichols MA, Shay JW, Xiong Y. 1994. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res 54:6078–82
    [Google Scholar]
  81. Lozano-Torres B, Galiana I, Rovira M, Garrido E, Chaib S et al. 2017. An OFF-ON two-photon fluorescent probe for tracking cell senescence in vivo. J. Am. Chem. Soc. 139:8808–11
    [Google Scholar]
  82. Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF et al. 2013. Non-cell-autonomous tumor suppression by p53. Cell 153:449–60
    [Google Scholar]
  83. Marcoux S, Le ON, Langlois-Pelletier C, Laverdiere C, Hatami A et al. 2013. Expression of the senescence marker p16INK4a in skin biopsies of acute lymphoblastic leukemia survivors: a pilot study. Radiat. Oncol. 8:252
    [Google Scholar]
  84. Marin I, Boix O, Garcia-Garijo A, Sirois I, Caballe A et al. 2022. Induction of senescence renders cancer cells highly immunogenic. bioRxiv 2022.06.05.494912. https://doi.org/10.1101/2022.06.05.494912
  85. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA et al. 2007. Programmed anuclear cell death delimits platelet life span. Cell 128:1173–86
    [Google Scholar]
  86. Meng Y, Efimova EV, Hamzeh KW, Darga TE, Mauceri HJ et al. 2012. Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine. Mol. Ther. 20:1046–55
    [Google Scholar]
  87. Mitin N, Nyrop KA, Strum SL, Knecht A, Carey LA et al. 2022. A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer. NPJ Breast Cancer 8:103
    [Google Scholar]
  88. Mitry MA, Laurent D, Keith BL, Sira E, Eisenberg CA et al. 2020. Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity. Am. J. Physiol. Cell Physiol. 318:C380–91
    [Google Scholar]
  89. Morin GB. 1989. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59:521–29
    [Google Scholar]
  90. Muss HB, Smitherman A, Wood WA, Nyrop K, Tuchman S et al. 2020. p16 a biomarker of aging and tolerance for cancer therapy. Transl. Cancer Res. 9:5732–42
    [Google Scholar]
  91. Narita M, Nunez S, Heard E, Narita M, Lin AW et al. 2003. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–16
    [Google Scholar]
  92. Ness KK, Kaste SC, Zhu L, Pui CH, Jeha S et al. 2015. Skeletal, neuromuscular and fitness impairments among children with newly diagnosed acute lymphoblastic leukemia. Leuk. Lymphoma 56:1004–11
    [Google Scholar]
  93. Nicolas AM, Pesic M, Engel E, Ziegler PK, Diefenhardt M et al. 2022. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell 40:168–84.e13
    [Google Scholar]
  94. Nijwening JH, Geutjes EJ, Bernards R, Beijersbergen RL. 2011. The histone demethylase Jarid1b (Kdm5b) is a novel component of the Rb pathway and associates with E2f-target genes in MEFs during senescence. PLOS ONE 6:e25235
    [Google Scholar]
  95. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. 2009. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. PNAS 106:17031–36
    [Google Scholar]
  96. Ovadya Y, Landsberger T, Leins H, Vadai E, Gal H et al. 2018. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9:5435
    [Google Scholar]
  97. Paffenholz SV, Salvagno C, Ho YJ, Limjoco M, Baslan T et al. 2022. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer. PNAS 119:e2117754119
    [Google Scholar]
  98. Paramos-de-Carvalho D, Jacinto A, Saúde L 2021. The right time for senescence. eLife 10:e72449
    [Google Scholar]
  99. Parry D, Bates S, Mann DJ, Peters G. 1995. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J 14:503–11
    [Google Scholar]
  100. Peng X, Wu Y, Brouwer U, van Vliet T, Wang B et al. 2020. Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche. Cell Death Dis 11:854
    [Google Scholar]
  101. Pereira BI, Devine OP, Vukmanovic-Stejic M, Chambers ES, Subramanian P et al. 2019. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 10:2387
    [Google Scholar]
  102. Poblocka M, Bassey AL, Smith VM, Falcicchio M, Manso AS et al. 2021. Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker. Sci. Rep. 11:20358
    [Google Scholar]
  103. Prasanna PG, Citrin DE, Hildesheim J, Ahmed MM, Venkatachalam S et al. 2021. Therapy-induced senescence: opportunities to improve anticancer therapy. J. Natl. Cancer Inst. 113:1285–98
    [Google Scholar]
  104. Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y et al. 2016. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat. Commun. 7:13363
    [Google Scholar]
  105. Roberson RS, Kussick SJ, Vallieres E, Chen SY, Wu DY. 2005. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res 65:2795–803
    [Google Scholar]
  106. Rodier F, Campisi J. 2011. Four faces of cellular senescence. J. Cell Biol. 192:547–56
    [Google Scholar]
  107. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP et al. 2009. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11:973–79
    [Google Scholar]
  108. Roninson IB. 2003. Tumor cell senescence in cancer treatment. Cancer Res 63:2705–15
    [Google Scholar]
  109. Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL et al. 2016. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7:11762
    [Google Scholar]
  110. Ruscetti M, Leibold J, Bott MJ, Fennell M, Kulick A et al. 2018. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362:1416–22
    [Google Scholar]
  111. Ruscetti M, Morris JP IV, Mezzadra R, Russell J, Leibold J et al. 2020. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181:424–41.e21
    [Google Scholar]
  112. Sagiv A, Burton DG, Moshayev Z, Vadai E, Wensveen F et al. 2016. NKG2D ligands mediate immunosurveillance of senescent cells. Aging 8:328–44
    [Google Scholar]
  113. Saleh T, Alhesa A, Al-Balas M, Abuelaish O, Mansour A et al. 2021. Expression of therapy-induced senescence markers in breast cancer samples upon incomplete response to neoadjuvant chemotherapy. Biosci. Rep. 41:bsr20210079
    [Google Scholar]
  114. Saleh T, Bloukh S, Carpenter VJ, Alwohoush E, Bakeer J et al. 2020a. Therapy-induced senescence: An “old” friend becomes the enemy. Cancers 12:822
    [Google Scholar]
  115. Saleh T, Carpenter VJ, Tyutyunyk-Massey L, Murray G, Leverson JD et al. 2020b. Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-XL–BAX interaction. Mol. Oncol. 14:2504–19
    [Google Scholar]
  116. Salminen A. 2021. Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases. Ageing Res. Rev. 67:101280
    [Google Scholar]
  117. Samaraweera L, Adomako A, Rodriguez-Gabin A, McDaid HM. 2017. A novel indication for Panobinostat as a senolytic drug in NSCLC and HNSCC. Sci. Rep. 7:1900
    [Google Scholar]
  118. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E et al. 2002. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–46First report that senescence may contribute to the efficacy of common anticancer therapies.
    [Google Scholar]
  119. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. 1997. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602Discovery of oncogene-induced senescence as a tumor-suppressive mechanism that is disabled by cooperating oncogenes.
    [Google Scholar]
  120. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW et al. 2017. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 18:895–903
    [Google Scholar]
  121. Shay JW, West MD, Wright WE. 1992. Re-expression of senescent markers in deinduced reversibly immortalized cells. Exp. Gerontol 27:477–92Discovery that DNA tumor viruses induce senescence bypass through inhibition of p53 and pRb by SV40 T antigen.
    [Google Scholar]
  122. Smitherman AB, Wood WA, Mitin N, Ayer Miller VL, Deal AM et al. 2020. Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailty. Cancer 126:4975–83
    [Google Scholar]
  123. Soysouvanh F, Benadjaoud MA, Dos Santos M, Mondini M, Lavigne J et al. 2020. Stereotactic lung irradiation in mice promotes long-term senescence and lung injury. Int. J. Radiat. Oncol. Biol. Phys. 106:1017–27
    [Google Scholar]
  124. Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y et al. 2021. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat. Aging 1:1117–26
    [Google Scholar]
  125. Sun Q, Guo Y, Liu X, Czauderna F, Carr MI et al. 2019. Therapeutic implications of p53 status on cancer cell fate following exposure to ionizing radiation and the DNA-PK inhibitor M3814. Mol. Cancer Res. 17:2457–68
    [Google Scholar]
  126. Tasdemir N, Banito A, Roe JS, Alonso-Curbelo D, Camiolo M et al. 2016. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov 6:612–29Demonstration that epigenetic remodeling mediates SASP-dependent immune surveillance.
    [Google Scholar]
  127. te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. 2002. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62:1876–83
    [Google Scholar]
  128. Tordella L, Khan S, Hohmeyer A, Banito A, Klotz S et al. 2016. SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer. Genes Dev 30:2187–98
    [Google Scholar]
  129. Triana-Martinez F, Picallos-Rabina P, Da Silva-Alvarez S, Pietrocola F, Llanos S et al. 2019. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun. 10:4731
    [Google Scholar]
  130. Tubita A, Lombardi Z, Tusa I, Lazzeretti A, Sgrignani G et al. 2022. Inhibition of ERK5 elicits cellular senescence in melanoma via the cyclin-dependent kinase inhibitor p21. Cancer Res 82:447–57
    [Google Scholar]
  131. Vinagre J, Almeida A, Populo H, Batista R, Lyra J et al. 2013. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 4:2185
    [Google Scholar]
  132. von Kobbe C. 2019. Targeting senescent cells: approaches, opportunities, challenges. Aging 11:12844–61
    [Google Scholar]
  133. Wakita M, Takahashi A, Sano O, Loo TM, Imai Y et al. 2020. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat. Commun. 11:1935
    [Google Scholar]
  134. Wang C, Vegna S, Jin H, Benedict B, Lieftink C et al. 2019. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 574:268–72
    [Google Scholar]
  135. Wang H, Wang Z, Huang Y, Zhou Y, Sheng X et al. 2019. Senolytics (DQ) mitigates radiation ulcers by removing senescent cells. Front. Oncol. 9:1576
    [Google Scholar]
  136. Wang L, Lankhorst L, Bernards R. 2022. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer 22:340–55
    [Google Scholar]
  137. Wang L, Leite de Oliveira R, Wang C, Fernandes Neto JM, Mainardi S et al. 2017. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep . 21:773–83Introduction of one-two punch therapy combining a senescence inducer with a senolytic agent.
    [Google Scholar]
  138. Wei J, Montalvo-Ortiz W, Yu L, Krasco A, Ebstein S et al. 2021. Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses. Sci. Immunol. 6:eabg0117
    [Google Scholar]
  139. Wright WE, Pereira-Smith OM, Shay JW 1989. Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts. Mol. Cell. Biol. 9:3088–92Discovery that DNA tumor viruses extend the cultured lifespan of normal human fibroblasts by allowing cells to bypass senescence.
    [Google Scholar]
  140. Xu J, Patel NH, Saleh T, Cudjoe EK Jr., Alotaibi M et al. 2018. Differential radiation sensitivity in p53 wild-type and p53-deficient tumor cells associated with senescence but not apoptosis or (nonprotective) autophagy. Radiat. Res. 190:538–57
    [Google Scholar]
  141. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T et al. 2015. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4:e12997
    [Google Scholar]
  142. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK et al. 2018. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24:1246–56
    [Google Scholar]
  143. Xue W, Zender L, Miething C, Dickins RA, Hernando E et al. 2007. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–60First report demonstrating immune surveillance of senescent cells as a potent tumor-suppressive program.
    [Google Scholar]
  144. Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y et al. 2016. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7:11190
    [Google Scholar]
  145. Yousefzadeh MJ, Wilkinson JE, Hughes B, Gadela N, Ladiges WC et al. 2020. Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues. GeroScience 42:951–61
    [Google Scholar]
  146. Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. 2021. Recent advances in the discovery of senolytics. Mech. Ageing Dev. 200:111587
    [Google Scholar]
  147. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H et al. 2015. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–58
    [Google Scholar]
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