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Stromal senescence contributes to age-related increases in cancer

Nature Reviews Cancer volume 25, pages 781–800 (2025)Cite this article

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Abstract

Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners in the transformation process and response to therapy. However, aspects of ageing that are important and the degree to which they contribute to cancer remain obscure. One of the factors that impacts ageing is increased cellular senescence but it is important to note that ageing and cellular senescence are not synonymous. We highlight open questions, including if senescent cells have phenotypically distinct impacts in aged versus young tissue, or if it is the cell type that dictates the impact of senescence on tissue homeostasis and disease. Finally, it is probable that our current definition of cellular senescence encompasses more than one mechanistically distinct cellular state; thus, we highlight phenotypic differences that have been noted across cell types and tissues of origin. This Review focuses on the role that senescent stromal cells have in cancer, with a particular emphasis on fibroblasts given the amount of work that has focused on them.

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Fig. 1: Senescent or aged stromal cells and their secreted SASP factors contribute to tumour development and progression in various ways.
Fig. 2: Aged and senescent stromal cells impact the establishment and growth of metastasis.
Fig. 3: Immunosenescence and its impact on cancer progression.

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References

  1. Fawell, S. et al. Tat-mediated delivery of heterologous proteins into cells. Proc. Natl Acad. Sci. USA 91, 664–668 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Laconi, E., Marongiu, F. & DeGregori, J. Cancer as a disease of old age: changing mutational and microenvironmental landscapes. Br. J. Cancer 122, 943–952 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Idda, M. L. et al. Survey of senescent cell markers with age in human tissues. Aging 12, 4052–4066 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). First reports (along with Storer et al.) of cellular senescence having a crucial role in embryonic development.

    Article  CAS  PubMed  Google Scholar 

  10. Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). First reports (along with Munoz-Espin et al.) of cellular senescence having a crucial role in embryonic development.

    Article  CAS  PubMed  Google Scholar 

  11. Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wolstein, J. M. et al. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am. J. Physiol. Ren. Physiol. 299, F1486–F1495 (2010).

    Article  CAS  Google Scholar 

  15. Li, Y. et al. Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix Biol. 55, 35–48 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tuttle, C. S. L. et al. Cellular senescence and chronological age in various human tissues: a systematic review and meta-analysis. Aging Cell 19, e13083 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). Report showing that naturally arising senescent cells limit tumour growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schmitt, C. A., Wang, B. & Demaria, M. Senescence and cancer — role and therapeutic opportunities. Nat. Rev. Clin. Oncol. 19, 619–636 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ye, J. et al. Senescent CAFs mediate immunosuppression and drive breast cancer progression. Cancer Discov. 14, 1302–1323 (2024). Report of senescent CAFs driving breast cancer progression by manipulating natural killer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Belle, J. I. et al. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer Discov. 14, 1324–1355 (2024). Report of senescent CAFs driving pancreatic cancer progression by manipulating macrophages and T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Assouline, B. et al. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice. Nat. Commun. 15, 6162 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mellone, M. et al. Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis. Aging 9, 114–132 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Loo, T. M. et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522–538 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Lee, J. Y. et al. Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity. Preprint at bioRxiv https://doi.org/10.1101/2024.07.29.605645 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Haston, S. et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell 41, 1242–1260.e6 (2023). Reports (along with Prieto et al.) of senescent immune cells impacting cancer progression.

    Article  CAS  PubMed  Google Scholar 

  29. Prieto, L. I. et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell 41, 1261–1275.e6 (2023). Reports (along with Haston et al.) of senescent immune cells impacting cancer progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001). Report showing that senescent fibroblasts promote tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Freund, A., Orjalo, A. V., Desprez, P. Y. & Campisi, J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, H. A. et al. Senescence rewires microenvironment sensing to facilitate antitumor immunity. Cancer Discov. 13, 432–453 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Romesser, P. B. & Lowe, S. W. The potent and paradoxical biology of cellular senescence in cancer. Annu. Rev. Cancer Biol. 7, 207–228 (2023).

    Article  Google Scholar 

  36. Hoare, M. & Narita, M. The power behind the throne: senescence and the hallmarks of cancer. Annu. Rev. Cancer Biol. 2, 175–194 (2018).

    Article  Google Scholar 

  37. Wang, L., Lankhorst, L. & Bernards, R. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer 22, 340–355 (2022).

    Article  CAS  PubMed  Google Scholar 

  38. Domen, A. et al. Cellular senescence in cancer: clinical detection and prognostic implications. J. Exp. Clin. Cancer Res. 41, 360 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021).

    Article  PubMed  Google Scholar 

  41. Victorelli, S. et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature 622, 627–636 (2023). Report showing that mitochondrial dysfunction drives SASP production.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Davalos, A. R. et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ashraf, H. M., Fernandez, B. & Spencer, S. L. The intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal. Nat. Commun. 14, 4527 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lopez-Polo, V. et al. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells. Nat. Commun. 15, 7378 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). Report demonstrating that autocrine signalling enforces oncogene-induced cellular senescence.

    Article  CAS  PubMed  Google Scholar 

  49. Coppe, J. P. et al. Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell Biol. 5, 741–747 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016). Report showing that senescent fibroblasts manipulate the local immune response to promote tumour growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fane, M. & Weeraratna, A. T. How the ageing microenvironment influences tumour progression. Nat. Rev. Cancer 20, 89–106 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Jochems, F. et al. The Cancer SENESCopedia: a delineation of cancer cell senescence. Cell Rep. 36, 109441 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chibaya, L. et al. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance. Nat. Cancer 4, 872–892 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  PubMed  Google Scholar 

  59. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  60. Lavie, D., Ben-Shmuel, A., Erez, N. & Scherz-Shouval, R. Cancer-associated fibroblasts in the single-cell era. Nat. Cancer 3, 793–807 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sebastian, A. et al. Single-cell transcriptomic analysis of tumor-derived fibroblasts and normal tissue-resident fibroblasts reveals fibroblast heterogeneity in breast cancer. Cancers 12, 1307 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Coppe, J. P., Kauser, K., Campisi, J. & Beausejour, C. M. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281, 29568–29574 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Liu, D. & Hornsby, P. J. Fibroblast stimulation of blood vessel development and cancer cell invasion in a subrenal capsule xenograft model: stress-induced premature senescence does not increase effect. Neoplasia 9, 418–426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hüser, L. et al. Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma. Cell Rep. 43, 114721 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Carbone, C. et al. Angiopoietin-like proteins in angiogenesis, inflammation and cancer. Int. J. Mol. Sci. 19, 431 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Nguyen, H. T. et al. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence. Nanotechnology 28, 095101 (2017).

    Article  PubMed  Google Scholar 

  69. Thapa, R. K. et al. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Sci. Rep. 7, 43299 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cox, T. R. The matrix in cancer. Nat. Rev. Cancer 21, 217–238 (2021).

    Article  CAS  PubMed  Google Scholar 

  71. Liu, D. & Hornsby, P. J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 67, 3117–3126 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Papadopoulou, A. & Kletsas, D. Human lung fibroblasts prematurely senescent after exposure to ionizing radiation enhance the growth of malignant lung epithelial cells in vitro and in vivo. Int. J. Oncol. 39, 989–999 (2011).

    CAS  PubMed  Google Scholar 

  73. Liakou, E. et al. Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-beta. Aging 8, 1650–1669 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ecker, B. L. et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov. 9, 82–95 (2019). Reports (along with Kaur et al. (2019)) of fibroblasts from older individuals promoting tumour development by modulating ECM integrity.

    Article  CAS  PubMed  Google Scholar 

  75. Kaur, A. et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov. 9, 64–81 (2019). Reports (along with Ecker et al.) of fibroblasts from older individuals promoting tumour development by modulating ECM integrity.

    Article  CAS  PubMed  Google Scholar 

  76. Takeda, K., Gosiewska, A. & Peterkofsky, B. Similar, but not identical, modulation of expression of extracellular matrix components during in vitro and in vivo aging of human skin fibroblasts. J. Cell Physiol. 153, 450–459 (1992).

    Article  CAS  PubMed  Google Scholar 

  77. Mavrogonatou, E., Pratsinis, H. & Kletsas, D. The role of senescence in cancer development. Semin. Cancer Biol. 62, 182–191 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Ju, J. A. et al. Hypoxia selectively enhances integrin alpha(5)beta(1) receptor expression in breast cancer to promote metastasis. Mol. Cancer Res. 15, 723–734 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li, H. et al. Senescent fibroblasts generate a CAF phenotype through the Stat3 pathway. Genes 13, 1579 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Howes, A. M. et al. Fibroblast senescence-associated extracellular matrix promotes heterogeneous lung niche. Apl. Bioeng. 8, 026119 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Calhoun, C. et al. Senescent cells contribute to the physiological remodeling of aged lungs. J. Gerontol. A Biol. Sci. Med. Sci. 71, 153–160 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Butcher, D. T., Alliston, T. & Weaver, V. M. A tense situation: forcing tumour progression. Nat. Rev. Cancer 9, 108–122 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Malik, R. et al. Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2. Matrix Biol. 81, 50–69 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Wu, B. et al. Stiff matrix induces exosome secretion to promote tumour growth. Nat. Cell Biol. 25, 415–424 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rafaeva, M. et al. Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression. Front. Immunol. 14, 1154528 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Choi, H. R. et al. Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix. Aging Cell 10, 148–157 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Kortlever, R. M., Higgins, P. J. & Bernards, R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat. Cell Biol. 8, 877–884 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hiebert, P. et al. Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome. Dev. Cell 46, 145–161.e10 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Nicolas, A. M. et al. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell 40, 168–184.e13 (2022).

    Article  CAS  PubMed  Google Scholar 

  92. Krishnamurty, A. T. & Turley, S. J. Lymph node stromal cells: cartographers of the immune system. Nat. Immunol. 21, 369–380 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Sturmlechner, I. et al. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science 374, eabb3420 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Marin, I. et al. Cellular senescence is immunogenic and promotes antitumor immunity. Cancer Discov. 13, 410–431 (2023).

    Article  CAS  PubMed  Google Scholar 

  97. Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 10, 2387 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Lau, L., Porciuncula, A., Yu, A., Iwakura, Y. & David, G. Uncoupling the senescence-associated secretory phenotype from cell cycle exit via interleukin-1 inactivation unveils its protumorigenic role. Mol. Cell Biol. 39, e00586-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Majewska, J. et al. p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells. Nat. Cell Biol. 26, 1336–1345 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Buque, A. et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat. Commun. 11, 3819 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Witkiewicz, A. K. et al. Association of RB/p16-pathway perturbations with DCIS recurrence: dependence on tumor versus tissue microenvironment. Am. J. Pathol. 179, 1171–1178 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yang, L. Y. et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J. Hematol. Oncol. 13, 3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Pazolli, E. et al. Senescent stromal-derived osteopontin promotes preneoplastic cell growth. Cancer Res. 69, 1230–1239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Luo, X., Ruhland, M. K., Pazolli, E., Lind, A. C. & Stewart, S. A. Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway. Mol. Cancer Res. 9, 1018–1029 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Eyman, D., Damodarasamy, M., Plymate, S. R. & Reed, M. J. CCL5 secreted by senescent aged fibroblasts induces proliferation of prostate epithelial cells and expression of genes that modulate angiogenesis. J. Cell Physiol. 220, 376–381 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bavik, C. et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 66, 794–802 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Meguro, S. et al. Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion. Nat. Aging 4, 1582–1597 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zabransky, D. J. et al. Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Res. 84, 1221–1236 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Alicea, G. M. et al. Changes in aged fibroblast lipid metabolism induce age-dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov. 10, 1282–1295 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Alicea, G. M. et al. Age-related increases in IGFBP2 increase melanoma cell invasion and lipid synthesis. Cancer Res. Commun. 4, 1908–1918 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Coppe, J. P. et al. A role for fibroblasts in mediating the effects of tobacco-induced epithelial cell growth and invasion. Mol. Cancer Res. 6, 1085–1098 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ortiz-Montero, P., Londono-Vallejo, A. & Vernot, J. P. Senescence-associated IL-6 and IL-8 cytokines induce a self- and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Commun. Signal. 15, 17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Butler, J. M., Kobayashi, H. & Rafii, S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat. Rev. Cancer 10, 138–146 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wieland, E. et al. Endothelial Notch1 activity facilitates metastasis. Cancer Cell 31, 355–367 (2017).

    Article  CAS  PubMed  Google Scholar 

  117. Li, X. et al. Mesenchymal/stromal stem cells: necessary factors in tumour progression. Cell Death Discov. 8, 333 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Di, G. H. et al. IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells. PLoS One 9, e113572 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Ghosh, D. et al. Senescent mesenchymal stem cells remodel extracellular matrix driving breast cancer cells to a more-invasive phenotype. J. Cell Sci. 133, jcs232470 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Salam, R. et al. Cellular senescence in malignant cells promotes tumor progression in mouse and patient glioblastoma. Nat. Commun. 14, 441 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fletcher-Sananikone, E. et al. Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence. Cancer Res. 81, 5935–5947 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Beck, B. et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478, 399–403 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ma, L., He, X., Fu, Y., Ge, S. & Yang, Z. Senescent endothelial cells promote liver metastasis of uveal melanoma in single-cell resolution. J. Transl. Med. 22, 605 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chung, A. S., Lee, J. & Ferrara, N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat. Rev. Cancer 10, 505–514 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Ferrara, N. & Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Wildiers, H. et al. Multicenter phase II randomized trial evaluating antiangiogenic therapy with sunitinib as consolidation after objective response to taxane chemotherapy in women with HER2-negative metastatic breast cancer. Breast Cancer Res. Treat. 123, 463–469 (2010).

    Article  CAS  PubMed  Google Scholar 

  128. Wang, D. et al. Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence. Breast Cancer Res. 22, 103 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ferjancic, S. et al. VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice. Blood 121, 3289–3297 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Okahara, H., Yagita, H., Miyake, K. & Okumura, K. Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor alpha enhancement of experimental metastasis. Cancer Res. 54, 3233–3236 (1994).

    CAS  PubMed  Google Scholar 

  131. Tichet, M. et al. Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nat. Commun. 6, 6993 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Perkins, D. W. et al. Therapy-induced normal tissue damage promotes breast cancer metastasis. iScience 27, 108503 (2024).

    Article  CAS  PubMed  Google Scholar 

  133. Barkan, D. et al. Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 70, 5706–5716 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Turrell, F. K. et al. Age-associated microenvironmental changes highlight the role of PDGF-C in ER+ breast cancer metastatic relapse. Nat. Cancer 4, 468–484 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2017). Report of chemotherapy-induced cellular senescence driving tumour progression.

    Article  CAS  PubMed  Google Scholar 

  136. Fane, M. E. et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 606, 396–405 (2022). Report of aged stromal cells driving reactivation of dormant tumour cells from melanoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Fornetti, J., Welm, A. L. & Stewart, S. A. Understanding the bone in cancer metastasis. J. Bone Min. Res. 33, 2099–2113 (2018).

    Article  CAS  Google Scholar 

  138. Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yuan, X. et al. Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells. Theranostics 11, 1429–1445 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Li, X. Q., Lu, J. T., Tan, C. C., Wang, Q. S. & Feng, Y. M. RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization. Cancer Lett. 380, 78–86 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Guo, S. et al. The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis. Mol. Cancer 22, 193 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Weitzmann, M. N. & Pacifici, R. Estrogen deficiency and bone loss: an inflammatory tale. J. Clin. Invest. 116, 1186–1194 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Luo, X. et al. Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep. 14, 82–92 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Kaur, J. et al. Single-cell transcriptomic analysis identifies senescent osteocytes that trigger bone destruction in breast cancer metastasis. Cancer Res. 84, 3936–3952 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Clezardin, P. Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res. 13, 207 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lian, J., Yue, Y., Yu, W. & Zhang, Y. Immunosenescence: a key player in cancer development. J. Hematol. Oncol. 13, 151 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Yang, L., Li, A., Lei, Q. & Zhang, Y. Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment. J. Hematol. Oncol. 12, 125 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Nasi, M. et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 5, 167–175 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. Palmer, D. B. The effect of age on thymic function. Front. Immunol. 4, 316 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Wang, W., Thomas, R., Sizova, O. & Su, D. M. Thymic function associated with cancer development, relapse, and antitumor immunity — a mini-review. Front. Immunol. 11, 773 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Godfrey, D. I., Koay, H. F., McCluskey, J. & Gherardin, N. A. The biology and functional importance of MAIT cells. Nat. Immunol. 20, 1110–1128 (2019).

    Article  CAS  PubMed  Google Scholar 

  153. Hale, J. S., Boursalian, T. E., Turk, G. L. & Fink, P. J. Thymic output in aged mice. Proc. Natl Acad. Sci. USA 103, 8447–8452 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Petrie, H. T. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol. Rev. 189, 8–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Rezzani, R., Nardo, L., Favero, G., Peroni, M. & Rodella, L. F. Thymus and aging: morphological, radiological, and functional overview. Age 36, 313–351 (2014).

    Article  PubMed  Google Scholar 

  156. Murray, J. M. et al. Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty. Immunol. Cell Biol. 81, 487–495 (2003).

    Article  PubMed  Google Scholar 

  157. Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30, 366–373 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ostrand-Rosenberg, S., Horn, L. A. & Haile, S. T. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J. Immunol. 193, 3835–3841 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Sato, K., Kato, A., Sekai, M., Hamazaki, Y. & Minato, N. Physiologic thymic involution underlies age-dependent accumulation of senescence-associated CD4+ T cells. J. Immunol. 199, 138–148 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Pawelec, G. Does patient age influence anti-cancer immunity? Semin. Immunopathol. 41, 125–131 (2019).

    Article  CAS  PubMed  Google Scholar 

  161. Linton, P. J. & Dorshkind, K. Age-related changes in lymphocyte development and function. Nat. Immunol. 5, 133–139 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Palmer, S., Albergante, L., Blackburn, C. C. & Newman, T. J. Thymic involution and rising disease incidence with age. Proc. Natl Acad. Sci. USA 115, 1883–1888 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Liu, Y. et al. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 8, 439–448 (2009). Demonstrated that p16 can be used as a biomarker for ageing.

    Article  CAS  PubMed  Google Scholar 

  164. Kientega, T. et al. Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship. Blood Cancer J. 14, 96 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Lagou, M. K., Anastasiadou, D. P. & Karagiannis, G. S. A proposed link between acute thymic involution and late adverse effects of chemotherapy. Front. Immunol. 13, 933547 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Frasca, D., Diaz, A., Romero, M., Landin, A. M. & Blomberg, B. B. Age effects on B cells and humoral immunity in humans. Ageing Res. Rev. 10, 330–335 (2011).

    Article  CAS  PubMed  Google Scholar 

  167. Weyand, C. M., Brandes, J. C., Schmidt, D., Fulbright, J. W. & Goronzy, J. J. Functional properties of CD4+ CD28– T cells in the aging immune system. Mech. Ageing Dev. 102, 131–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  168. Shalapour, S. & Karin, M. The neglected brothers come of age: B cells and cancer. Semin. Immunol. 52, 101479 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lund, F. E. & Randall, T. D. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat. Rev. Immunol. 10, 236–247 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Germain, C. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am. J. Respir. Crit. Care Med. 189, 832–844 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Li, Y., Terauchi, M., Vikulina, T., Roser-Page, S. & Weitzmann, M. N. B cell production of both OPG and RANKL is significantly increased in aged mice. Open Bone J. 6, 8–17 (2014).

    PubMed  PubMed Central  Google Scholar 

  175. Teitelbaum, S. L. Bone resorption by osteoclasts. Science 289, 1504–1508 (2000).

    Article  CAS  PubMed  Google Scholar 

  176. Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  178. Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).

    Article  CAS  PubMed  Google Scholar 

  179. Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Golonka, R. M., Xiao, X., Abokor, A. A., Joe, B. & Vijay-Kumar, M. Altered nutrient status reprograms host inflammation and metabolic health via gut microbiota. J. Nutr. Biochem. 80, 108360 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Montecino-Rodriguez, E., Berent-Maoz, B. & Dorshkind, K. Causes, consequences, and reversal of immune system aging. J. Clin. Invest. 123, 958–965 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147.e16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Sanchez-Correa, B. et al. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies? Cancer Immunol. Immunother. 65, 453–463 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 69, S4–S9 (2014).

    Article  Google Scholar 

  185. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115.e12 (2021).

    Article  CAS  PubMed  Google Scholar 

  187. Vasto, S. et al. Inflammation, ageing and cancer. Mech. Ageing Dev. 130, 40–45 (2009).

    Article  CAS  PubMed  Google Scholar 

  188. Antonangeli, F., Zingoni, A., Soriani, A. & Santoni, A. Senescent cells: living or dying is a matter of NK cells. J. Leukoc. Biol. 105, 1275–1283 (2019).

    Article  CAS  PubMed  Google Scholar 

  189. Sagiv, A. et al. NKG2D ligands mediate immunosurveillance of senescent cells. Aging 8, 328–344 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Hazeldine, J., Hampson, P. & Lord, J. M. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 11, 751–759 (2012).

    Article  CAS  PubMed  Google Scholar 

  191. Hazeldine, J. & Lord, J. M. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res. Rev. 12, 1069–1078 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Brubaker, A. L., Rendon, J. L., Ramirez, L., Choudhry, M. A. & Kovacs, E. J. Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J. Immunol. 190, 1746–1757 (2013).

    Article  CAS  PubMed  Google Scholar 

  193. Bancaro, N. et al. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer. Cancer Cell 41, 602–619.e11 (2023).

    Article  CAS  PubMed  Google Scholar 

  194. Hall, B. M. et al. Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging 8, 1294–1315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kumar, R., Sharma, A., Padwad, Y. & Sharma, R. Preadipocyte secretory factors differentially modulate murine macrophage functions during aging which are reversed by the application of phytochemical EGCG. Biogerontology 21, 325–343 (2020).

    Article  CAS  PubMed  Google Scholar 

  196. Liu, J. Y. et al. Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence. Proc. Natl Acad. Sci. USA 116, 2603–2611 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Prattichizzo, F. et al. Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages. Redox Biol. 15, 170–181 (2018).

    Article  CAS  PubMed  Google Scholar 

  198. Wang, Q. et al. Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging. Int. J. Oral Sci. 13, 11 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Liu, Z. et al. Immunosenescence: molecular mechanisms and diseases. Signal. Transduct. Target. Ther. 8, 200 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Martinez-Zamudio, R. I. et al. Senescence-associated beta-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans. Aging Cell 20, e13344 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Wolf, N. K., Kissiov, D. U. & Raulet, D. H. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat. Rev. Immunol. 23, 90–105 (2023).

    Article  CAS  PubMed  Google Scholar 

  202. Monti, M. et al. Plasmacytoid dendritic cells at the forefront of anti-cancer immunity: rewiring strategies for tumor microenvironment remodeling. J. Exp. Clin. Cancer Res. 43, 196 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Robinson, A., Han, C. Z., Glass, C. K. & Pollard, J. W. Monocyte regulation in homeostasis and malignancy. Trends Immunol. 42, 104–119 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Kroemer, G. & Zitvogel, L. CD4+ T cells at the center of inflammaging. Cell Metab. 32, 4–5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Lee, G. R. The balance of Th17 versus Treg cells in autoimmunity. Int. J. Mol. Sci. 19, 730 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Campbell, D. J. & Koch, M. A. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat. Rev. Immunol. 11, 119–130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Gao, Y. et al. Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc. Natl Acad. Sci. USA 112, E3246–E3254 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Minato, N., Hattori, M. & Hamazaki, Y. Physiology and pathology of T-cell aging. Int. Immunol. 32, 223–231 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Zhao, Y., Shao, Q. & Peng, G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol. Immunol. 17, 27–35 (2020).

    Article  CAS  PubMed  Google Scholar 

  210. Reiser, J. & Banerjee, A. Effector, memory, and dysfunctional CD8+ T cell fates in the antitumor immune response. J. Immunol. Res. 2016, 8941260 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  212. Henson, S. M. et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 113, 6619–6628 (2009).

    Article  CAS  PubMed  Google Scholar 

  213. Muroyama, Y. 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. Preprint at bioRxiv https://doi.org/10.1101/2022.04.16.488552 (2022).

    Article  Google Scholar 

  214. Vallejo, A. N. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol. Rev. 205, 158–169 (2005).

    Article  CAS  PubMed  Google Scholar 

  215. Appay, V. et al. HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Gupta, P. K. et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 11, e1005177 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Zhang, N. N. et al. Accumulation mechanisms of CD4+CD25+FOXP3+ regulatory T cells in EBV-associated gastric carcinoma. Sci. Rep. 5, 18057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Shang, B., Liu, Y., Jiang, S. J. & Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci. Rep. 5, 15179 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Zhang, S. et al. Analysis of CD8+ Treg cells in patients with ovarian cancer: a possible mechanism for immune impairment. Cell Mol. Immunol. 12, 580–591 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Moreira, A. et al. Senescence markers: predictive for response to checkpoint inhibitors. Int. J. Cancer 144, 1147–1150 (2019).

    Article  CAS  PubMed  Google Scholar 

  221. Effros, R. B. Replicative senescence in the immune system: impact of the Hayflick limit on T-cell function in the elderly. Am. J. Hum. Genet. 62, 1003–1007 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Zhu, X. & Niedermann, G. Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells. Oncoscience 2, 476–482 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Mehta, P. H. et al. Choice of activation protocol impacts the yield and quality of CAR T cell product, particularly with older individuals. Clin. Transl. Immunol. 13, e70016 (2024).

    Article  CAS  Google Scholar 

  224. Janelle, V. et al. p16INK4a regulates cellular senescence in PD-1-expressing human T cells. Front. Immunol. 12, 698565 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Zhang, Y. et al. Interleukin-7 inhibits tumor-induced CD27-CD28- suppressor T cells: implications for cancer immunotherapy. Clin. Cancer Res. 17, 4975–4986 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. D’Ambrosio, M. & Gil, J. Reshaping of the tumor microenvironment by cellular senescence: an opportunity for senotherapies. Dev. Cell 58, 1007–1021 (2023).

    Article  PubMed  Google Scholar 

  228. Xiong, J. et al. Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes. Clin. Transl. Med. 14, e1772 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  231. Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).

    Article  CAS  PubMed  Google Scholar 

  233. Saleh, T. et al. Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-X(L) -BAX interaction. Mol. Oncol. 14, 2504–2519 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Fleury, H. et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat. Commun. 10, 2556 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Kolodkin-Gal, D. et al. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut 71, 345–355 (2022).

    Article  CAS  PubMed  Google Scholar 

  236. Guccini, I. et al. Senescence reprogramming by TIMP1 deficiency promotes prostate cancer metastasis. Cancer Cell 39, 68–82.e69 (2021).

    Article  CAS  PubMed  Google Scholar 

  237. Troiani, M. et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nat. Commun. 13, 2177 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Lafontaine, J. et al. Senolytic targeting of Bcl-2 anti-apoptotic family increases cell death in irradiated sarcoma cells. Cancers 13, 386 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Kovacovicova, K. et al. Senolytic Cocktail Dasatinib+Quercetin (D+Q) does not enhance the efficacy of senescence-inducing chemotherapy in liver cancer. Front. Oncol. 8, 459 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Lee, J. Y. et al. An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis. J. Clin. Invest. 134, e173371 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Amor, C. et al. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat. Aging 4, 336–349 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Wang, T. W. et al. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes. Nature 611, 358–364 (2022).

    Article  CAS  PubMed  Google Scholar 

  245. Hall, B. M. et al. p16(Ink4a) and senescence-associated beta-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging 9, 1867–1884 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Besancenot, R. et al. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol. 8, e1000476 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Li, C. et al. Programmed cell senescence in skeleton during late puberty. Nat. Commun. 8, 1312 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  248. Grosse, L. et al. Defined p16High senescent cell types are indispensable for mouse healthspan. Cell Metab. 32, 87–99.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  249. Alspach, E. et al. p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov. 4, 716–729 (2014). Established that the p38 MAPK stress pathway is crucial to maintaining the SASP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Laberge, R. M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049–1061 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Murali, B. et al. Inhibition of the stromal p38MAPK/MK2 pathway limits breast cancer metastases and chemotherapy-induced bone loss. Cancer Res. 78, 5618–5630 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Hu, Q. et al. Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma. Cell Death Dis. 11, 925 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).

    Article  CAS  PubMed  Google Scholar 

  255. Colucci, M. et al. Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells. Cancer Cell 42, 646–661.e49 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Yamagishi, R. et al. Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma. Sci. Immunol. 7, eabl7209 (2022).

    Article  CAS  PubMed  Google Scholar 

  257. Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell 152, 340–351 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Reyes, N. S. et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science 378, 192–201 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Zhao, H. et al. Identifying specific functional roles for senescence across cell types. Cell 187, 7314–7334.e21 (2024).

    Article  CAS  PubMed  Google Scholar 

  260. Ohtani, N. et al. Visualizing the dynamics of p21(Waf1/Cip1) cyclin-dependent kinase inhibitor expression in living animals. Proc. Natl Acad. Sci. USA 104, 15034–15039 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Chandra, A. et al. Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity. Aging Cell 21, e13602 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Omori, S. et al. Generation of a p16 reporter mouse and its use to characterize and target p16high cells in vivo. Cell Metab. 32, 814–828.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  263. Wang, H. et al. Senolytics (DQ) mitigates radiation ulcers by removing senescent cells. Front. Oncol. 9, 1576 (2019).

    Article  PubMed  Google Scholar 

  264. Wang, C. et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 574, 268–272 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Triana-Martinez, F. et al. Identification and characterization of cardiac glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  266. Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Yang, D. et al. NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Sci. Transl. Med. 15, eadd1951 (2023).

    Article  CAS  PubMed  Google Scholar 

  268. Hwang, H. J. et al. Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation. Nat. Commun. 16, 353 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Chaib, S. et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat. Cancer 5, 448–462 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Yu, Y. C. et al. Radiation-induced senescence in securin-deficient cancer cells promotes cell invasion involving the IL-6/STAT3 and PDGF-BB/PDGFR pathways. Sci. Rep. 3, 1675 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  271. Zhang, Y. et al. Mitogen-activated protein kinase p38 and retinoblastoma protein signalling is required for DNA damage-mediated formation of senescence-associated heterochromatic foci in tumour cells. FEBS J. 280, 4625–4639 (2013).

    Article  CAS  PubMed  Google Scholar 

  272. Alimirah, F. et al. Cellular senescence promotes skin carcinogenesis through p38MAPK and p44/42MAPK signaling. Cancer Res. 80, 3606–3619 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Su, D. et al. Role of p38 MAPK pathway in BMP4-mediated Smad-dependent premature senescence in lung cancer cells. Biochem. J. 433, 333–343 (2011).

    Article  CAS  PubMed  Google Scholar 

  274. Alimbetov, D. et al. Small molecule targeting of the p38/Mk2 stress signaling pathways to improve cancer treatment. BMC Cancer 23, 895 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Grierson, P. M. et al. The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress. Sci. Transl. Med. 13, eabb5445 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12, 489–498 (2013).

    Article  CAS  PubMed  Google Scholar 

  277. Sugimoto, Y. et al. Metformin suppresses esophageal cancer progression through the radiation-induced cellular senescence of cancer-associated fibroblasts. Oncol. Rep. 52, 129 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Takasugi, M. et al. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01 AG059244, CA217208, R56AG088264 (S.A.S.). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014, is the awarding and administrating acquisition office, and this was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program, under award no. BC181712. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This work was also supported by the Cancer Research Foundation and the Siteman Cancer Center Investment Program (NCI Cancer Center Support Grant P30CA091842), Fashion Footwear Association of New York, and the Alvin J. Siteman Cancer Center Siteman Investment Program (supported by The Foundation for Barnes-Jewish Hospital, Cancer Frontier Fund) to S.A.S. J.Y. and A.M. were supported by NIH F31 grant CA271721 and Cancer Biology Pathway of Siteman Cancer Center, which was funded by an NCI T32 grant CA113275.

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Author notes

  1. These authors contributed equally: Jiayu Ye, Anupama Melam.

Authors and Affiliations

  1. Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA

    Jiayu Ye, Anupama Melam & Sheila A. Stewart

  2. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Sheila A. Stewart

  3. Siteman Cancer Center, St Louis, MO, USA

    Sheila A. Stewart

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  2. Anupama Melam
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J.Y. and A.M. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Sheila A. Stewart.

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Nature Reviews Cancer thanks Marcus Ruscetti, Naoko Ohtani and Jesus Gil, who co-reviewed with Boyang Ma, for their contribution to the peer review of this work.

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Glossary

Bone turnover

A dynamic process of bone resorption by osteoclasts and bone formation by osteoblasts to maintain bone tissue homeostasis.

Chimeric antigen receptor (CAR) T cells

Genetically engineered T lymphocytes that recognize and eliminate cells expressing specific antigens.

Class switch recombination

A DNA recombination process that allows B cells to alter their antibody isotype while maintaining antigen specificity.

Complement system

A system consists of a cascade of plasma proteins that react with one another to enhance immune responses via opsonization, cell lysis and inflammation.

M1 polarization

A process by which macrophages differentiate into a pro-inflammatory state that enhances phagocytosis and cytokine production to promote immune responses against pathogens and tumour cells.

Macroautophagy

A process in which cytoplasmic proteins are sequestered in autophagosomes and transported to lysosomes for degradation and recycling.

Minority mitochondrial outer membrane permeabilization

(miMOMP). A process where, upon sublethal stress stimulation, the outer membrane of a few mitochondria within a cell become permeable and leak out proteins and mitochondrial DNA to cytosol.

Proteostasis

A process that maintains protein homeostasis within a cell through active regulation of protein synthesis, folding, trafficking and degradation.

Secondary harmonic generation

Biological materials with specific molecular orientation to generate frequency-doubled light from incident light can be visualized via secondary harmonic generation imaging microscopy.

Senolytics

Drugs that kill senescent cells, often by poorly understood mechanisms.

Shed proteins

Membrane-bound proteins can be cleaved and released into extracellular space as shed proteins to initiate or regulate downstream signalling.

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Ye, J., Melam, A. & Stewart, S.A. Stromal senescence contributes to age-related increases in cancer. Nat Rev Cancer 25, 781–800 (2025). https://doi.org/10.1038/s41568-025-00840-9

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