Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes

Abstract

	•Senescence-associated secretory phenotype (SASP) secretion from senescent tumour cells significantly impacts cancer progression and biology.
	•SASP is involved in regulating the remodelling of the tumour microenvironment, including immune microenvironment, vascular, extracellular matrix and cancer stem cells.
	•Senotherapeutics, such as senolytic, senomorphic, nanotherapy and senolytic vaccines, hold promise for enhancing cancer treatment efficacy.

Keywords

cell senescence / SASP / senolytic / tumour microenvironment

References

[1] GabaiY, Assouline B, Ben-PorathI. Senescent stromal cells: roles in the tumor microenvironment. Trends Cancer. 2023; 9: 28-41.

[2] ColladoM, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010; 10: 51-57.

[3] DimriGP, Testori A, AcostaM, CampisiJ. Replicative senescence, aging and growth-regulatory transcription factors. Biol Signals. 1996; 5: 154-162.

[4] DimriGP, LeeX, BasileG, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Nat Acad Sci USA. 1995; 92: 9363-9367.

[5] ChoKA, RyuSJ, OhYS, et al. Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem. 2004; 279: 42270-42278.

[6] NaritaM, NunezS, HeardE, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113: 703-716.

[7] HewittG, JurkD, MarquesFD, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun. 2012; 3: 708.

[8] LiuP, LiF, LinJ, et al. m(6)A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype. Nat Cell Biol. 2021; 23: 355-365.

[9] WangL, Lankhorst L, BernardsR. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022; 22: 340-355.

[10] CoppeJP, Desprez PY, KrtolicaA, CampisiJ. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5: 99-118.

[11] DemirciD, DayancB, MaziFA, Senturk S. The Jekyll and Hyde of cellular senescence in cancer. Cells. 2021; 10: 208.

[12] LiuH, ZhaoH, SunY. Tumor microenvironment and cellular senescence: understanding therapeutic resistance and harnessing strategies. Semin Cancer Biol. 2022; 86: 769-781.

[13] SerranoM, LinAW, McCurrachME, Beach D, LoweSW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88: 593-602.

[14] LiuXL, LiuJL, XuYC, et al. Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic PIK3CA(H1047R) accompanied with pro-tumorigenic secretome. Int J Cancer. 2019; 145: 817-829.

[15] KangTW, YevsaT, WollerN, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011; 479: 547-551.

[16] IannelloA, Thompson TW, ArdolinoM, LoweSW, RauletDH. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med. 2013; 210: 2057-2069.

[17] EggertT, WolterK, JiJ, et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell. 2016; 30: 533-547.

[18] TosoA, Revandkar A, Di MitriD, et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 2014; 9: 75-89.

[19] ChibayaL, SnyderJ, RuscettiM. Senescence and the tumor-immune landscape: implications for cancer immunotherapy. Semin Cancer Biol. 2022; 86: 827-845.

[20] ChenZ, Trotman LC, ShafferD, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005; 436: 725-730.

[21] YoshidaA, LeeEK, DiehlJA. Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6. Cancer Res. 2016; 76: 2990-3002.

[22] AnnovazziL, MellaiM, SchifferD. Chemotherapeutic drugs: DNA damage and repair in glioblastoma. Cancers. 2017; 9: 57.

[23] FarrellNP. Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets. Chem Soc Rev. 2015; 44: 8773-8785.

[24] ChienY, Scuoppo C, WangX, et al. Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev. 2011; 25: 2125-2136.

[25] HaoX, ZhaoB, ZhouW, et al. Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype. iScience. 2021; 24: 102016.

[26] AntonangeliF, Soriani A, RicciB, et al. Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells. Oncoimmunology. 2016; 5: e1218105.

[27] BorrelliC, RicciB, VulpisE, et al. Drug-induced senescent multiple myeloma cells elicit NK cell proliferation by direct or exosome-mediated IL15 trans-presentation. Cancer Immunol Res. 2018; 6: 860-869.

[28] ChaibS, Lopez-Dominguez JA, Lalinde-GutierrezM, et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat Cancer. 2024; 5: 448-462.

[29] SanoffHK, DealAM, KrishnamurthyJ, et al. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst. 2014; 106: dju057.

[30] MitinN, NyropKA, StrumSL, et al. A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer. NPJ Breast Cancer. 2022; 8: 103.

[31] WoodWA, Krishnamurthy J, MitinN, et al. Chemotherapy and stem cell transplantation increase p16(INK4a) expression, a biomarker of T-cell aging. EBioMedicine. 2016; 11: 227-238.

[32] BruniE, Cazzetta V, DonadonM, et al. Chemotherapy accelerates immune-senescence and functional impairments of Vdelta2(pos) T cells in elderly patients affected by liver metastatic colorectal cancer. J Immunother Cancer. 2019; 7: 347.

[33] ZhangJ, HeT, XueL, GuoH. Senescent T cells: a potential biomarker and target for cancer therapy. EBioMedicine. 2021; 68: 103409.

[34] PetroniG, Cantley LC, SantambrogioL, FormentiSC, Galluzzi L. Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer. Nat Rev Clin Oncol. 2022; 19: 114-131.

[35] JonesKR, ElmoreLW, Jackson-CookC, et al. p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int J Radiat Biol. 2005; 81: 445-458.

[36] JeonHY, KimJK, HamSW, et al. Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype. Tumour Biol. 2016; 37: 5857-5867.

[37] KansaraM, LeongHS, LinDM, et al. Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. J Clin Invest. 2013; 123: 5351-5360.

[38] FangC, MoF, LiuL, et al. Oxidized mitochondrial DNA sensing by STING signaling promotes the antitumor effect of an irradiated immunogenic cancer cell vaccine. Cell Mol Immunol. 2021; 18: 2211-2223.

[39] TeseiA, Arienti C, BossiG, et al. TP53 drives abscopal effect by secretion of senescence-associated molecular signals in non-small cell lung cancer. J Exp Clin Cancer Res. 2021; 40: 89.

[40] RuhlandMK, LozaAJ, CapiettoAH, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016; 7: 11762.

[41] AmundsonSA, GraceMB, McLelandCB, et al. Human in vivo radiation-induced biomarkers: gene expression changes in radiotherapy patients. Cancer Res. 2004; 64: 6368-6371.

[42] XuX, WeiF, XiaoL, et al. High proportion of circulating CD8 + CD28-senescent T cells is an independent predictor of distant metastasis in nasopharyngeal canrcinoma after radiotherapy. J Transl Med. 2023; 21: 64.

[43] ParkSS, ChoiYW, KimJH, Kim HS, ParkTJ. Senescent tumor cells: an overlooked adversary in the battle against cancer. Exp Mol Med. 2021; 53: 1834-1841.

[44] WagnerV, GilJ. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene. 2020; 39: 5165-5176.

[45] Jerby-ArnonL, ShahP, CuocoMS, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018; 175: 984-997. e24.

[46] CrozierL, FoyR, AdibR, et al. CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Mol Cell. 2023; 83: 4062-4077. e5.

[47] ZhuX, FuZ, DutchakK, et al. Cotargeting CDK4/6 and BRD4 promotes senescence and ferroptosis sensitivity in cancer. Cancer Res. 2024; 84: 1333-1351.

[48] RuscettiM, Leibold J, BottMJ, et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science. 2018; 362: 1416-1422.

[49] Torres-GuzmanR, Calsina B, HermosoA, et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget. 2017; 8: 69493-69507.

[50] RuscettiM, MorrisJPT, MezzadraR, et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell. 2020; 181: 424-441. e21.

[51] TangH, FanX, XingJ, et al. NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging. 2015; 7: 1143-1158.

[52] SongP, ChenX, ZhangP, Zhou Y, ZhouR. miR-200b/MYBL2/CDK1 suppresses proliferation and induces senescence through cell cycle arrest in ovine granulosa cells. Theriogenology. 2023; 207: 19-30.

[53] MullersE, Silva Cascales H, BurdovaK, MacurekL, Lindqvist A. Residual Cdk1/2 activity after DNA damage promotes senescence. Aging Cell. 2017; 16: 575-584.

[54] WangQ, WuPC, RobersonRS, et al. Survivin and escaping in therapy-induced cellular senescence. Int J Cancer. 2011; 128: 1546-1558.

[55] DietrichC, TrubA, AhnA, et al. INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors. Cancer Discov. 2024; 14: 446-467.

[56] WuJ, YuanY, Long PrielDA, et al. Phase I study of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas. Clin Cancer Res. 2021; 27: 3298-3306.

[57] Le RhunE, von Achenbach C, LohmannB, et al. Profound, durable and MGMT-independent sensitivity of glioblastoma cells to cyclin-dependent kinase inhibition. Int J Cancer. 2019; 145: 242-253.

[58] WilsonGA, VuinaK, SavaG, et al. Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition. Mol Cell. 2023; 83: 4078-4092. e6.

[59] PorterDC, Farmaki E, AltiliaS, et al. Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Proc Nat Acad Sci USA. 2012; 109: 13799-13804.

[60] GaoJ, Pickett HA. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. Nat Rev Cancer. 2022; 22: 515-532.

[61] Salimi-JedaA, Badrzadeh F, EsghaeiM, AbdoliA. The role of telomerase and viruses interaction in cancer development, and telomerase-dependent therapeutic approaches. Cancer Treat Res Commun. 2021; 27: 100323.

[62] KuriharaY, Watanabe Y, OnimatsuH, et al. Telomerase-specific virotheranostics for human head and neck cancer. Clin Cancer Res. 2009; 15: 2335-2343.

[63] WangYG, WangJH, ZhangYH, Gu Q, LiuXY. Antitumor effect of a novel adeno-associated virus vector targeting to telomerase activity in tumor cells. Acta Biochim Biophy Sin. 2004; 36: 492-500.

[64] BurchettKM, YanY, OuelletteMM. Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells. PLoS One. 2014; 9: e85155.

[65] WangL, YinH, HuangS, et al. Bortezomib induces cellular senescence in A549 lung cancer cells by stimulating telomere shortening. Hum Exp Toxicol. 2022; 41: 9603271221124094.

[66] MaciejewskaN, Olszewski M, JuraszJ, et al. Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres. Cell Death Dis. 2022; 13: 1005.

[67] LeeYH, ChenYY, YehYL, Wang YJ, ChenRJ. Stilbene compounds inhibit tumor growth by the induction of cellular senescence and the inhibition of telomerase activity. Int J Mol Sci. 2019; 20: 2716.

[68] LeungAWY, Anantha M, DragowskaWH, WehbeM, BallyMB. Copper-CX-5461: a novel liposomal formulation for a small molecule rRNA synthesis inhibitor. J Control Release. 2018; 286: 1-9.

[69] LopatinaN, Haskell JF, AndrewsLG, PooleJC, Saldanha S, TollefsbolT. Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J Cell Biochem. 2002; 84: 324-334.

[70] JohnstoneSE, Gladyshev VN, AryeeMJ, BernsteinBE. Epigenetic clocks, aging, and cancer. Science. 2022; 378: 1276-1277.

[71] LewinskaA, Adamczyk-Grochala J, DeregowskaA, WnukM. Sulforaphane-induced cell cycle arrest and senescence are accompanied by DNA hypomethylation and changes in microRNA profile in breast cancer cells. Theranostics. 2017; 7: 3461-3477.

[72] ItoT, TeoYV, EvansSA, Neretti N, SedivyJM. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage-and histone methylation-dependent pathways. Cell Rep. 2018; 22: 3480-3492.

[73] ManCH, LamW, DangCC, et al. Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML. Blood. 2023; 142: 2002-2015.

[74] JiangZ, LiW, HuX, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20: 806-815.

[75] OkuniN, HonmaY, UranoT, Tamura K. Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation. Mol Biol Rep. 2022; 49: 3519-3529.

[76] WarnonC, Bouhjar K, NinaneN, et al. HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts. Aging. 2021; 13: 17978-18005.

[77] AlmeidaLO, Guimaraes DM, MartinsMD, et al. Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence. Stem Cell Res. 2017; 21: 94-105.

[78] JiaHJ, GeY, XiaJ, ShiYL, WangXB. Belinostat (PXD101) resists UVB irradiation-induced cellular senescence and skin photoaging. Biochem Biophys Res Commun. 2022; 627: 122-129.

[79] FagetDV, RenQ, StewartSA. Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer. 2019; 19: 439-453.

[80] RodierF, CoppeJP, PatilCK, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009; 11: 973-979.

[81] KangC, XuQ, MartinTD, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015; 349: aaa5612.

[82] TakahashiA, ImaiY, YamakoshiK, et al. DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells. Mol Cell. 2012; 45: 123-131.

[83] ChenH, RuizPD, McKimpsonWM, Novikov L, KitsisRN, GambleMJ. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol Cell. 2015; 59: 719-731.

[84] ContrepoisK, Coudereau C, BenayounBA, et al. Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat Commun. 2017; 8: 14995.

[85] PazolliE, Alspach E, MilczarekA, PriorJ, Piwnica-Worms D, StewartSA. Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res. 2012; 72: 2251-2261.

[86] HayakawaT, IwaiM, AokiS, et al. SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation. PLoS One. 2015; 10: e0116480.

[87] AirdKM, Iwasaki O, KossenkovAV, et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol. 2016; 215: 325-334.

[88] CapellBC, DrakeAM, ZhuJ, et al. MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev. 2016; 30: 321-336.

[89] TasdemirN, BanitoA, RoeJS, et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 2016; 6: 612-629.

[90] ChenHA, HoYJ, MezzadraR, et al. Senescence rewires microenvironment sensing to facilitate antitumor immunity. Cancer Discov. 2023; 13: 432-453.

[91] ChungEJ, KwonS, ReedyJL, et al. IGF-1 receptor signaling regulates type II pneumocyte senescence and resulting macrophage polarization in lung fibrosis. Int J Radiat Oncol Biol Phys. 2021; 110: 526-538.

[92] MazzoniM, MauroG, ErreniM, et al. Senescent thyrocytes and thyroid tumor cells induce M2-like macrophage polarization of human monocytes via a PGE2-dependent mechanism. J Exp Clin Cancer Res. 2019; 38: 208.

[93] ZhangC, GuX, PanM, YuanQ, ChengH. Senescent thyroid tumor cells promote their migration by inducing the polarization of M2-like macrophages. Clin Transl Oncol. 2021; 23: 1253-1261.

[94] LiuH, ZhaoD, LiH, et al. Blocking iASPP/Nrf2/M-CSF axis improves anti-cancer effect of chemotherapy-induced senescence by attenuating M2 polarization. Cell Death Dis. 2022; 13: 166.

[95] LiuR, CuiJ, SunY, et al. Autophagy deficiency promotes M1 macrophage polarization to exacerbate acute liver injury via ATG5 repression during aging. Cell Death Discov. 2021; 7: 397.

[96] LujambioA, AkkariL, SimonJ, et al. Non-cell-autonomous tumor suppression by p53. Cell. 2013; 153: 449-460.

[97] MazzoniM, MauroG, MinoliL, et al. Senescent thyrocytes, similarly to thyroid tumor cells, elicit M2-like macrophage polarization in vivo. Biology. 2021; 10: 985.

[98] MarinI, BoixO, Garcia-GarijoA, et al. Cellular senescence is immunogenic and promotes antitumor immunity. Cancer Discov. 2023; 13: 410-431.

[99] GoelS, DeCristo MJ, WattAC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017; 548: 471-475.

[100] XueW, ZenderL, MiethingC, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445: 656-660.

[101] GuanX, LaPakKM, HennesseyRC, et al. Stromal senescence by prolonged CDK4/6 inhibition potentiates tumor growth. Mol Cancer Res. 2017; 15: 237-249.

[102] TakeuchiH, KonnaiS, MaekawaN, et al. Canine transforming growth factor-beta receptor 2-Ig: a potential candidate biologic for melanoma treatment that reverses transforming growth factor-beta1 immunosuppression. Front Vet Sci. 2021; 8: 656715.

[103] NelsonA, LukacsJD, JohnstonB. The current landscape of NKT cell immunotherapy and the hills ahead. Cancers. 2021; 13: 5174.

[104] MossanenJC, Kohlhepp M, WehrA, et al. CXCR6 inhibits hepatocarcinogenesis by promoting natural killer T-and CD4(+) T-cell-dependent control of senescence. Gastroenterology. 2019; 156: 1877-1889. e4.

[105] HaverkampJM, CristSA, ElzeyBD, Cimen C, RatliffTL. In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Eur J Immunol. 2011; 41: 749-759.

[106] Di MitriD, TosoA, ChenJJ, et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature. 2014; 515: 134-137.

[107] GiordoR, WehbeZ, PaliogiannisP, EidAH, Mangoni AA, PintusG. Nano-targeting vascular remodeling in cancer: recent developments and future directions. Semin Cancer Biol. 2022; 86: 784-804.

[108] KrtolicaA, Parrinello S, LockettS, DesprezPY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Nat Acad Sci USA. 2001; 98: 12072-12077.

[109] CoppeJP, KauserK, CampisiJ, Beausejour CM. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006; 281: 29568-29574.

[110] Mikula-PietrasikJ, Sosinska P, NaumowiczE, et al. Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo. Clin Exp Metastasis. 2016; 33: 15-27.

[111] GuoD, MaD, LiuP, LanJ, LiuZ, LiuQ. DNASE1L3 arrests tumor angiogenesis by impairing the senescence-associated secretory phenotype in response to stress. Aging. 2021; 13: 9874-9899.

[112] CaiL, XuS, PiaoC, Qiu S, LiH, DuJ. Adiponectin induces CXCL1 secretion from cancer cells and promotes tumor angiogenesis by inducing stromal fibroblast senescence. Mol Carcinog. 2016; 55: 1796-1806.

[113] YinK, PattenD, GoughS, et al. Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance. Genes Dev. 2022; 36: 533-549.

[114] ChenY, McAndrews KM, KalluriR. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021; 18: 792-804.

[115] YangG, RosenDG, ZhangZ, et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Nat Acad Sci USA. 2006; 103: 16472-16477.

[116] ChuL, QuY, AnY, et al. Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer. Cell Death Dis. 2022; 13: 155.

[117] PerrottKM, WileyCD, DesprezPY, Campisi J. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. GeroScience. 2017; 39: 161-173.

[118] SharmaM, HunterKD, FonsecaFP, Radhakrishnan R. Emerging role of cellular senescence in the pathogenesis of oral submucous fibrosis and its malignant transformation. Head Neck. 2021; 43: 3153-3164.

[119] WeiSC, FattetL, TsaiJH, et al. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015; 17: 678-688.

[120] LeightJL, Wozniak MA, ChenS, LynchML, ChenCS. Matrix rigidity regulates a switch between TGF-beta1-induced apoptosis and epithelial-mesenchymal transition. Mol Biol Cell. 2012; 23: 781-791.

[121] SchraderJ, Gordon-Walker TT, AucottRL, et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology. 2011; 53: 1192-1205.

[122] LeaskA. A centralized communication network: recent insights into the role of the cancer associated fibroblast in the development of drug resistance in tumors. Semin Cell Dev Biol. 2020; 101: 111-114.

[123] Nicolas-BoludaA, Vaquero J, VimeuxL, et al. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment. eLife. 2021; 10: e58688.

[124] MilanovicM, YuY, SchmittCA. The senescence-stemness alliance—a cancer-hijacked regeneration principle. Trends Cell Biol. 2018; 28: 1049-1061.

[125] MilanovicM, FanDNY, BelenkiD, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018; 553: 96-100.

[126] KarabiciciM, Alptekin S, Firtina KaragonlarZ, ErdalE. Doxorubicin-induced senescence promotes stemness and tumorigenicity in EpCAM-/CD133-nonstem cell population in hepatocellular carcinoma cell line, HuH-7. Mol Oncol. 2021; 15: 2185-2202.

[127] Ortiz-MonteroP, Londono-Vallejo A, VernotJP. 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. 2017; 15: 17.

[128] KimSY, KangJW, SongX, et al. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signalling. 2013; 25: 961-969.

[129] Ospina-MunozN, VernotJP. Partial acquisition of stemness properties in tumorspheres obtained from interleukin-8-treated MCF-7 cells. Tumour Biol. 2020; 42: 1010428320979438.

[130] MaX, ChenJ, LiuJ, et al. IL-8/CXCR2 mediates tropism of human bone marrow-derived mesenchymal stem cells toward CD133(+) /CD44(+) Colon cancer stem cells. J Cell Physiol. 2021; 236: 3114-3128.

[131] DuX, ZhangX, QiZ, et al. HELLS modulates the stemness of intrahepatic cholangiocarcinoma through promoting senescence-associated secretory phenotype. Comput Struct Biotechnol J. 2023; 21: 5174-5185.

[132] Fauziya GuptaA, NadafA, AhmadS, et al. Dasatinib: a potential tyrosine kinase inhibitor to fight against multiple cancer malignancies. Med Oncol. 2023; 40: 173.

[133] TangSM, DengXT, ZhouJ, Li QP, GeXX, MiaoL. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother. 2020; 121: 109604.

[134] KumarRM, KumarH, BhattT, et al. Fisetin in cancer: attributes, developmental aspects, and nanotherapeutics. Pharmaceuticals. 2023; 16: 196.

[135] FleuryH, Malaquin N, TuV, et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat Commun. 2019; 10: 2556.

[136] Gonzalez-GualdaE, Paez-Ribes M, Lozano-TorresB, et al. Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell. 2020; 19: e13142.

[137] PrietoLI, Sturmlechner I, GravesSI, et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell. 2023; 41: 1261-1275. e6.

[138] Fletcher-SananikoneE, Kanji S, TomimatsuN, et al. Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence. Cancer Res. 2021; 81: 5935-5947.

[139] HastonS, Gonzalez-Gualda E, MorsliS, et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell. 2023; 41: 1242-1260. e6.

[140] Kolodkin-GalD, Roitman L, OvadyaY, et al. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut. 2022; 71: 345-355.

[141] KangMH, KangYH, SzymanskaB, et al. Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood. 2007; 110: 2057-2066.

[142] TahirSK, YangX, AndersonMG, et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 2007; 67: 1176-1183.

[143] AdamovaB, RihovaK, PokludovaJ, Benes P, SmardaJ, NavratilovaJ. Synergistic cytotoxicity of perifosine and ABT-737 to colon cancer cells. J Cell Mol Med. 2023; 27: 76-88.

[144] TagschererKE, FasslA, CamposB, et al. Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene. 2008; 27: 6646-6656.

[145] GuerreroA, Herranz N, SunB, et al. Cardiac glycosides are broad-spectrum senolytics. Nat Metab. 2019; 1: 1074-1088.

[146] DeryabinPI, Shatrova AN, BorodkinaAV. Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides. Cell Mol Life Sci. 2021; 78: 7757-7776.

[147] BaarMP, BrandtRMC, PutavetDA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017; 169: 132-147. e16.

[148] XuQ, FuQ, LiZ, et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab. 2021; 3: 1706-1726.

[149] HerranzN, Gallage S, MelloneM, et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol. 2015; 17: 1205-1217.

[150] van VlietT, Varela-Eirin M, WangB, et al. Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression. Mol Cell. 2021; 81: 2041-2052. e6.

[151] MuraliB, RenQ, LuoX, et al. Inhibition of the stromal p38MAPK/MK2 pathway limits breast cancer metastases and chemotherapy-induced bone loss. Cancer Res. 2018; 78: 5618-5630.

[152] OrjaloAV, Bhaumik D, GenglerBK, ScottGK, Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Nat Acad Sci USA. 2009; 106: 17031-17036.

[153] PrattichizzoF, Giuliani A, RecchioniR, et al. Anti-TNF-alpha treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells. Oncotarget. 2016; 7: 11945-11958.

[154] KampanNC, XiangSD, McNallyOM, Stephens AN, QuinnMA, PlebanskiM. Immunotherapeutic interleukin-6 or interleukin-6 receptor blockade in cancer: challenges and opportunities. Curr Med Chem. 2018; 25: 4785-4806.

[155] WangH, WangZ, HuangY, et al. Senolytics (DQ) mitigates radiation ulcers by removing senescent cells. Front Oncol. 2019; 9: 1576.

[156] Di MiccoR, Krizhanovsky V, BakerD, d’Adda di FagagnaF. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol. 2021; 22: 75-95.

[157] LabergeRM, SunY, OrjaloAV, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015; 17: 1049-1061.

[158] RossiJF, LuZY, JourdanM, Klein B. Interleukin-6 as a therapeutic target. Clin Cancer Res. 2015; 21: 1248-1257.

[159] LewinskaA, WrobelK, BloniarzD, Adamczyk-Grochala J, WolowiecS, WnukM. Lapatinib-and fulvestrant-PAMAM dendrimer conjugates promote apoptosis in chemotherapy-induced senescent breast cancer cells with different receptor status. Biomater Adv. 2022; 140: 213047.

[160] Munoz-EspinD, RoviraM, GalianaI, et al. A versatile drug delivery system targeting senescent cells. EMBO Mol Med. 2018; 10: e9355.

[161] GalianaI, Lozano-Torres B, SanchoM, et al. Preclinical antitumor efficacy of senescence-inducing chemotherapy combined with a nanoSenolytic. J Control Release. 2020; 323: 624-634.

[162] ThapaRK, NguyenHT, JeongJH, et al. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Sci Rep. 2017; 7: 43299.

[163] JiP, WangC, LiuY, et al. Targeted clearance of senescent cells via engineered extracellular vesicles reprograms tumor immunosuppressive microenvironment. Adv Healthc Mater. 2024:e2400945.

[164] OuHL, Hoffmann R, Gonzalez-LopezC, DohertyGJ, Korkola JE, Munoz-EspinD. Cellular senescence in cancer: from mechanisms to detection. Mol Oncol. 2021; 15: 2634-2671.

[165] AmorC, FeuchtJ, LeiboldJ, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020; 583: 127-132.

[166] YangD, SunB, LiS, et al. NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Sci Transl Med. 2023; 15: eadd1951.

[167] SudaM, Shimizu I, KatsuumiG, et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging. 2021; 1: 1117-1126.

[168] KirklandJL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020; 288: 518-536.

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.