Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment

Abstract

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Keywords

cellular senescence / metabolic reprogramming / hypoxia / chronic inflammation / immunosuppressive tumor microenvironment / tumor-targeted therapy

References

[1] Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961; 25: 585-621.

[2] Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer. 2020; 20(2): 89-106.

[3] Huang W, Hickson LJ, Eirin A, Kirkland JL, Lerman LO. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol. 2022; 18(10): 611-27.

[4] Dou X, Fu Q, Long Q, Liu S, Zou Y, Fu D, et al. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy. Nat Metab. 2023; 5(11): 1887-910.

[5] Li F, Huangyang P, Burrows M, Guo K, Riscal R, Godfrey J, et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat Cell Biol. 2020; 22(6): 728-39.

[6] 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. 2021; 22(2): 75-95.

[7] Chen Z, Wang Z, Du Y, Shi H, Zhou W. The microbiota and aging microenvironment in pancreatic cancer: Cell origin and fate. Biochim Biophys Acta Rev Cancer. 2022; 1877(6): 188826.

[8] Liu H, Zhao H, Sun Y. Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. Semin Cancer Biol. 2022; 86(Pt 3): 769-81.

[9] Zhang JW, Zhang D, Yin HS, Zhang H, Hong KQ, Yuan JP, et al. Fusobacterium nucleatum promotes esophageal squamous cell carcinoma progression and chemoresistance by enhancing the secretion of chemotherapy-induced senescence-associated secretory phenotype via activation of DNA damage response pathway. Gut Microbes. 2023; 15(1): 2197836.

[10] Petroni G, Buqué A, Coussens LM, Galluzzi L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat Rev Drug Discov. 2022; 21(6): 440-62.

[11] Xiang X, Wang J, Lu D, Xu X. Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther. 2021; 6(1): 75.

[12] Lemos H, Huang L, Prendergast GC, Mellor AL. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat Rev Cancer. 2019; 19(3): 162-75.

[13] Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017; 17(9): 559-72.

[14] Weigel C, Maczis MA, Palladino END, Green CD, Maceyka M, Guo C, et al. Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer. Cancer Res. 2022.

[15] Liu Z, Liang Q, Ren Y, Guo C, Ge X, Wang L, et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther. 2023; 8(1): 200.

[16] Golomb L, Sagiv A, Pateras IS, Maly A, Krizhanovsky V, Gorgoulis VG, et al. Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy. Cell Death Differ. 2015; 22(11): 1764-74.

[17] Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, et al. Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab. 2016; 23(2): 303-14.

[18] Faget DV, Ren Q, Stewart SA. Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer. 2019; 19(8): 439-53.

[19] Carroll JE, Nakamura ZM, Small BJ, Zhou X, Cohen HJ, Ahles TA, et al. Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study. J Clin Oncol. 2022:Jco2200406.

[20] Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012; 16(6): 751-64.

[21] Bancaro N, Calì B, Troiani M, Elia AR, Arzola RA, Attanasio G, et al. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer. Cancer Cell. 2023; 41(3): 602-19.e11.

[22] Prieto LI, Sturmlechner I, Graves SI, Zhang C, Goplen NP, Yi ES, et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell. 2023; 41(7): 1261-75.e6.

[23] Lasry A, Ben-Neriah Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 2015; 36(4): 217-28.

[24] Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015; 21(12): 1424-35.

[25] Tie Y, Tang F, Wei YQ, Wei XW. Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol. 2022; 15(1): 61.

[26] Ye J, Ma C, Hsueh EC, Dou J, Mo W, Liu S, et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol Med. 2014; 6(10): 1294-311.

[27] Georgilis A, Klotz S, Hanley CJ, Herranz N, Weirich B, Morancho B, et al. PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. Cancer Cell. 2018; 34(1): 85-102.e9.

[28] Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017; 550(7676): 402-6.

[29] Dong F, Li R, Wang J, Zhang Y, Yao J, Jiang SH, et al. Hypoxia-dependent expression of MAP17 coordinates the Warburg effect to tumor growth in hepatocellular carcinoma. J Exp Clin Cancer Res. 2021; 40(1): 121.

[30] Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K, et al. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J Hematol Oncol. 2022; 15(1): 77.

[31] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646-74.

[32] Yu W, Lei Q, Yang L, Qin G, Liu S, Wang D, et al. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol. 2021; 14(1): 187.

[33] Ramello MC, Tosello Boari J, Canale FP, Mena HA, Negrotto S, Gastman B, et al. Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L. Cell Death Dis. 2014; 5(11): e1507.

[34] Wang SF, Tseng LM, Lee HC. Role of mitochondrial alterations in human cancer progression and cancer immunity. J Biomed Sci. 2023; 30(1): 61.

[35] Dubey S, Ghosh S, Goswami D, Ghatak D, De R. Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression. Biochem Pharmacol. 2023; 208: 115369.

[36] Sabbatinelli J, Prattichizzo F, Olivieri F, Procopio AD, Rippo MR, Giuliani A. Where Metabolism Meets Senescence: Focus on Endothelial Cells. Front Physiol. 2019; 10: 1523.

[37] Breitenbach M, Rinnerthaler M, Hartl J, Stincone A, Vowinckel J, Breitenbach-Koller H. et al. Mitochondria in ageing: there is metabolism beyond the ROS. FEMS Yeast Res. 2014; 14(1): 198-212.

[38] Kang W, Suzuki M, Saito T, Miyado K. Emerging Role of TCA Cycle-Related Enzymes in Human Diseases. Int J Mol Sci. 2021; 22(23).

[39] Song BS, Moon JS, Tian J, Lee HY, Sim BC, Kim SH, et al. Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion. J Immunother Cancer. 2022; 10(5).

[40] Farfariello V, Gordienko DV, Mesilmany L, Touil Y, Germain E, Fliniaux I, et al. TRPC3 shapes the ER-mitochondria Ca(2+) transfer characterizing tumour-promoting senescence. Nat Commun. 2022; 13(1): 956.

[41] Xiao AY, Maynard MR, Piett CG, Nagel ZD, Alexander JS, Kevil CG, et al. Sodium sulfide selectively induces oxidative stress, DNA damage, and mitochondrial dysfunction and radiosensitizes glioblastoma (GBM) cells. Redox Biol. 2019; 26: 101220.

[42] Mobet Y, Liu X, Liu T, Yu J, Yi P. Interplay Between m(6)A RNA Methylation and Regulation of Metabolism in Cancer. Front Cell Dev Biol. 2022; 10: 813581.

[43] Samuel M, Fonseka P, Sanwlani R, Gangoda L, Chee SH, Keerthikumar S, et al. Oral administration of bovine milk-derived extracellular vesicles induces senescence in the primary tumor but accelerates cancer metastasis. Nat Commun. 2021; 12(1): 3950.

[44] Li Z, Low V, Luga V, Sun J, Earlie E, Parang B, et al. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression. Nat Commun. 2022; 13(1): 6239.

[45] Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci. 2016; 41(3): 211-8.

[46] Riera-Domingo C, Audigé A, Granja S, Cheng WC, Ho PC, Baltazar F, et al. Immunity, Hypoxia, and Metabolism-th. Ménage à Trois of Cancer: Implications for Immunotherapy. Physiol Rev. 2020; 100(1): 1-102.

[47] Capparelli C, Guido C, Whitaker-Menezes D. Bonuccelli G, Balliet R, Pestell TG, et al. Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle. 2012; 11(12): 2285-302.

[48] Stegen S, Laperre K, Eelen G, Rinaldi G, Fraisl P, Torrekens S, et al. HIF-1α metabolically controls collagen synthesis and modification in chondrocytes. Nature. 2019; 565(7740): 511-5.

[49] Martínez-Zamudio RI, Robinson L, Roux PF, Bischof O. SnapShot: Cellular Senescence Pathways. Cell. 2017; 170(4): 816-.e1.

[50] Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell. 2015; 162(3): 552-63.

[51] Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ, Kojima N, et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol. 2018; 19(12): 1319-29.

[52] Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE. Lin Z, et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. Cell Cycle. 2011; 10(23): 4065-73.

[53] Zhou R, Ni W, Qin C, Zhou Y, Li Y, Huo J, et al. A functional loop between YTH domain family protein YTHDF3 mediated m(6)A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma. J Exp Clin Cancer Res. 2022; 41(1): 334.

[54] Liu X, Mo W, Ye J, Li L, Zhang Y, Hsueh EC, et al. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat Commun. 2018; 9(1): 249.

[55] Li PH, Zhang R, Cheng LQ, Liu JJ, Chen HZ. Metabolic regulation of immune cells in proinflammatory microenvironments and diseases during ageing. Ageing Res Rev. 2020; 64: 101165.

[56] Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, et al. NAD(+) metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol. 2019; 21(3): 397-407.

[57] Jakhar R, Crasta K. Exosomes as Emerging Pro-Tumorigenic Mediators of the Senescence-Associated Secretory Phenotype. Int J Mol Sci. 2019; 20(10).

[58] Takasugi M, Okada R, Takahashi A, Virya Chen D, Watanabe S, Hara E. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat Commun. 2017; 8: 15729.

[59] Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012; 482(7383): 53-8.

[60] Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, et al. Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy. Cell Rep. 2019; 29(1): 135-50.e9.

[61] Ma Y, Temkin SM, Hawkridge AM, Guo C, Wang W, Wang XY, et al. Fatty acid oxidation: An emerging facet of metabolic transformation in cancer. Cancer Lett. 2018; 435: 92-100.

[62] Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, Smans K. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res. 2013; 52(4): 585-9.

[63] Wright HJ, Hou J, Xu B, Cortez M, Potma EO, Tromberg BJ, et al. CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation. Proc Natl Acad Sci U S A. 2017; 114(32): E6556-e65.

[64] Gao A, Liu X, Lin W, Wang J, Wang S, Si F, et al. Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. J Immunother Cancer. 2021; 9(3).

[65] Chung YL, Wu ML. Promyelocytic leukaemia protein links DNA damage response and repair to hepatitis B virus-related hepatocarcinogenesis. J Pathol. 2013; 230(4): 377-87.

[66] Li XJ, Li QL, Ju LG, Zhao C, Zhao LS, Du JW, et al. Deficiency of Histone Methyltransferase SET Domain-Containing 2 in Liver Leads to Abnormal Lipid Metabolism and HCC. Hepatology. 2021; 73(5): 1797-815.

[67] Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, et al. Enhanced Lipid Accumulation and Metabolism Are Required for the Differentiation and Activation of Tumor-Associated Macrophages. Cancer Res. 2020; 80(7): 1438-50.

[68] Iwamoto H, Abe M, Yang Y, Cui D, Seki T, Nakamura M, et al. Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance. Cell Metab. 2018; 28(1): 104-17.e5.

[69] Makino Y, Hikita H, Fukumoto K, Sung JH, Sakano Y, Murai K, et al. Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non-Cell Autonomous Liver Carcinogenesis. Cancer Res. 2022; 82(16): 2860-73.

[70] Tan Y, Li J, Zhao G, Huang KC, Cardenas H, Wang Y, et al. Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells. Nat Commun. 2022; 13(1): 4554.

[71] Li X, Wang J, Wang L, Gao Y, Feng G, Li G, et al. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging. Signal Transduct Target Ther. 2022; 7(1): 162.

[72] Johnson ND, Conneely KN. The role of DNA methylation and hydroxymethylation in immunosenescence. Ageing Res Rev. 2019; 51: 11-23.

[73] Chen L, Zhang W, Chen D, Yang Q, Sun S, Dai Z, et al. RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis. Signal Transduct Target Ther. 2023; 8(1): 159.

[74] Bauwens E, Parée T, Meurant S, Bouriez I, Hannart C, Wéra AC, et al. Senescence Induced by UVB in Keratinocytes Impairs Amino Acids Balance. J Invest Dermatol. 2023; 143(4): 554-65.e9.

[75] Yamagishi R, Kamachi F, Nakamura M, Yamazaki S, Kamiya T, Takasugi M, et al. Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma. Sci Immunol. 2022; 7(72): eabl7209.

[76] Martinez-Outschoorn UE, Lisanti MP, Sotgia F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin Cancer Biol. 2014; 25: 47-60.

[77] Chung EJ, Kwon S, Reedy JL, White AO, Song JS, Hwang I, 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(2): 526-38.

[78] Baraibar MA, Hyzewicz J, Rogowska-Wrzesinska A. Bulteau AL, Prip-Buus C. Butler-Browne G, et al. Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes. Aging (Albany NY). 2016; 8(12): 3375-89.

[79] Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022; 40(2): 201-18.e9.

[80] Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016; 24(5): 657-71.

[81] Li X, Zhang Z, Zhang Y, Cao Y, Wei H, Wu Z. Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16(INK4a) inactivation. J Exp Clin Cancer Res. 2018; 37(1): 39.

[82] Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, et al. Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer. Cancer Immunol Res. 2020; 8(11): 1440-51.

[83] Zhang A, Xu Y, Xu H, Ren J, Meng T, Ni Y, et al. Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17. Theranostics. 2021; 11(8): 3839-52.

[84] Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019; 366(6468): 1013-21.

[85] Bertero T, Oldham WM, Grasset EM, Bourget I, Boulter E, Pisano S, et al. Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy. Cell Metab. 2019; 29(1): 124-40.e10.

[86] Yang C, Wu S, Mou Z, Zhou Q, Dai X, Ou Y, et al. Exosome-derived circTRPS1 promotes malignant phenotype and CD8+ T cell exhaustion in bladder cancer microenvironments. Mol Ther. 2022; 30(3): 1054-70.

[87] Pacifico F, Badolati N, Mellone S, Stornaiuolo M, Leonardi A, Crescenzi E. Glutamine promotes escape from therapy-induced senescence in tumor cells. Aging (Albany NY). 2021; 13(17): 20962-91.

[88] Yang S, Hwang S, Kim M, Seo SB, Lee JH, Jeong SM. Mitochondrial glutamine metabolism via GOT2 supports pancreatic cancer growth through senescence inhibition. Cell Death Dis. 2018; 9(2): 55.

[89] Davari K, Holland T, Prassmayer L, Longinotti G, Ganley KP, Pechilis LJ, et al. Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy. J Immunother Cancer. 2021; 9(3).

[90] Kishton RJ, Sukumar M, Restifo NP. Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy. Cell Metab. 2017; 26(1): 94-109.

[91] Legut M, Gajic Z, Guarino M, Daniloski Z, Rahman JA, Xue X, et al. A genome-scale screen for synthetic drivers of T cell proliferation. Nature. 2022; 603(7902): 728-35.

[92] Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021; 13(587).

[93] Yan C, Zheng L, Jiang S, Yang H, Guo J, Jiang LY, et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell. 2023.

[94] Rodriguez-Garcia M, Fortier JM, Barr FD, Wira CR. Aging impacts CD103(+) CD8(+) T cell presence and induction by dendritic cells in the genital tract. Aging Cell. 2018; 17(3): e12733.

[95] Dolfi DV, Duttagupta PA, Boesteanu AC, Mueller YM, Oliai CH, Borowski AB, et al. Dendritic cells and CD28 costimulation are required to sustain virus-specific CD8+ T cell responses during the effector phase in vivo. J Immunol. 2011; 186(8): 4599-608.

[96] Agrawal S, Ganguly S, Tran A, Sundaram P, Agrawal A. Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age. Aging (Albany NY). 2016; 8(6): 1223-35.

[97] Franco F, Jaccard A, Romero P, Yu YR, Ho PC. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab. 2020; 2(10): 1001-12.

[98] Xie F, Zhou X, Li H, Su P, Liu S, Li R, et al. USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII. Embo j. 2022; 41(16): e108791.

[99] Nishida M, Yamashita N, Ogawa T, Koseki K, Warabi E, Ohue T, et al. Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes. J Immunother Cancer. 2021; 9(9).

[100] Rawlings DJ, Metzler G, Wray-Dutra M. Jackson SW. Altered B cell signalling in autoimmunity. Nat Rev Immunol. 2017; 17(7): 421-36.

[101] Ren J, Lan T, Liu T, Liu Y, Shao B, Men K, et al. CXCL13 as a Novel Immune Checkpoint for Regulatory B Cells and Its Role in Tumor Metastasis. J Immunol. 2022; 208(10): 2425-35.

[102] Salminen A. Activation of immunosuppressive network in the aging process. Ageing Res Rev. 2020; 57: 100998.

[103] Wunderlich CM, Ackermann PJ, Ostermann AL, Adams-Quack P. Vogt MC, Tran ML, et al. Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment. Nat Commun. 2018; 9(1): 1646.

[104] Tomay F, Wells K, Duong L, Tsu JW, Dye DE, Radley-Crabb HG. et al. Aged neutrophils accumulate in lymphoid tissues from healthy elderly mice and infiltrate T-and B-cell zones. Immunol Cell Biol. 2018; 96(8): 831-40.

[105] Yu J, Angelin-Duclos C. Greenwood J, Liao J, Calame K. Transcriptional repression by blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase. Mol Cell Biol. 2000; 20(7): 2592-603.

[106] Dussault I, Miller SC. Decline in natural killer cell-mediated immunosurveillance in aging mice–a consequence of reduced cell production and tumor binding capacity. Mech Ageing Dev. 1994; 75(2): 115-29.

[107] Degos C, Heinemann M, Barrou J, Boucherit N, Lambaudie E, Savina A, et al. Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function. Front Immunol. 2019; 10: 877.

[108] Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, et al. Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell. 2016; 30(4): 533-47.

[109] Téllez-Bañuelos MC, González-Ochoa S, Ortiz-Lazareno PC. Rosas-Gonzalez VC, Gómez-Villela J, Haramati J. Low-dose endosulfan inhibits proliferation and induces senescence and pro-inflammatory cytokine production in human lymphocytes, preferentially impacting cytotoxic cells. J Immunotoxicol. 2019; 16(1): 173-81.

[110] Li S, Mirlekar B, Johnson BM, Brickey WJ, Wrobel JA, Yang N, et al. STING-induced regulatory B cells compromise NK function in cancer immunity. Nature. 2022; 610(7931): 373-80.

[111] Sarhan D, Palma M, Mao Y, Adamson L, Kiessling R, Mellstedt H, et al. Dendritic cell regulation of NK-cell responses involves lymphotoxin-α, IL-12, and TGF-β. Eur J Immunol. 2015; 45(6): 1783-93.

[112] Walle T, Kraske JA, Liao B, Lenoir B, Timke C, von Bohlen Und Halbach E, et al. Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8. Sci Adv. 2022; 8(12): eabh4050.

[113] Mossanen JC, Kohlhepp M, Wehr A, Krenkel O, Liepelt A, Roeth AA, et al. CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T-and CD4(+) T-Cell-Dependent Control of Senescence. Gastroenterology. 2019; 156(6): 1877-89.e4.

[114] Bachiller M, Perez-Amill L. Battram AM, Carné SC, Najjar A, Verhoeyen E, et al. NK cells enhance CAR-T cell antitumor efficacy by enhancing immune/tumor cells cluster formation and improving CAR-T cell fitness. J Immunother Cancer. 2021; 9(8).

[115] Shurin MR, Shurin GV, Chatta GS. Aging and the dendritic cell system: implications for cancer. Crit Rev Oncol Hematol. 2007; 64(2): 90-105.

[116] Wong CP, Magnusson KR, Ho E. Aging is associated with altered dendritic cells subset distribution and impaired proinflammatory cytokine production. Exp Gerontol. 2010; 45(2): 163-9.

[117] Chougnet CA, Thacker RI, Shehata HM, Hennies CM, Lehn MA, Lages CS, et al. Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction. J Immunol. 2015; 195(6): 2624-32.

[118] Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res. 2008; 68(15): 6341-9.

[119] Ventura MT, Casciaro M, Gangemi S, Buquicchio R. Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin Mol Allergy. 2017; 15: 21.

[120] Elsayed R, Elashiry M, Liu Y, El-Awady A. Hamrick M, Cutler CW. Porphyromonas gingivalis Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells. Front Cell Infect Microbiol. 2021; 11: 669989.

[121] Guo Z, Tilburgs T, Wong B, Strominger JL. Dysfunction of dendritic cells in aged C57BL/6 mice leads to failure of natural killer cell activation and of tumor eradication. Proc Natl Acad Sci U S A. 2014; 111(39): 14199-204.

[122] Lu T, Zhang Z, Bi Z, Lan T, Zeng H, Liu Y, et al. TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway. J Immunother Cancer. 2023; 11(3).

[123] Marin I, Boix O, Garcia-Garijo A. Sirois I, Caballe A, Zarzuela E, et al. Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity. Cancer Discov. 2023; 13(2): 410-31.

[124] Zhou J, Tang Z, Gao S, Li C, Feng Y, Zhou X. Tumor-Associated Macrophages: Recent Insights and Therapies. Front Oncol. 2020; 10: 188.

[125] Ryu S, Sidorov S, Ravussin E, Artyomov M, Iwasaki A, Wang A, et al. The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging. Immunity. 2022; 55(9): 1609-26.e7.

[126] Chen S, Saeed A, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther. 2023; 8(1): 207.

[127] Wang H, Fu H, Zhu R, Wu X, Ji X, Li X, et al. BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake. Aging (Albany NY). 2020; 12(10): 9240-59.

[128] van Beek AA, Van den Bossche J, Mastroberardino PG, de Winther MPJ, Leenen PJM. Metabolic Alterations in Aging Macrophages: Ingredients for Inflammaging? Trends Immunol. 2019; 40(2): 113-27.

[129] Mazzoni M, Mauro G, Erreni M, Romeo P, Minna E, Vizioli MG, 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(1): 208.

[130] Yang C, Wang Z, Li L, Zhang Z, Jin X, Wu P, et al. Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis. J Immunother Cancer. 2021; 9(10).

[131] Grieshaber-Bouyer R, Exner T, Hackert NS, Radtke FA, Jelinsky SA, Halyabar O, et al. Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint. Ann Rheum Dis. 2022; 81(6): 805-14.

[132] Ou B, Liu Y, Gao Z, Xu J, Yan Y, Li Y, et al. Senescent neutrophils-derived exosomal piRNA-17560 promotes chemoresistance and EMT of breast cancer via FTO-mediated m6A demethylation. Cell Death Dis. 2022; 13(10): 905.

[133] Mittmann LA, Haring F, Schaubächer JB, Hennel R, Smiljanov B, Zuchtriegel G, et al. Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression. J Immunother Cancer. 2021; 9(12).

[134] Cheng N, Bai X, Shu Y, Ahmad O, Shen P. Targeting tumor-associated macrophages as an antitumor strategy. Biochem Pharmacol. 2021; 183: 114354.

[135] Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018; 17(12): 887-904.

[136] Cardoso AP, Pinto ML, Pinto AT, Oliveira MI, Pinto MT, Gonçalves R, et al. Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. Oncogene. 2014; 33(16): 2123-33.

[137] Keane L, Antignano I, Riechers SP, Zollinger R, Dumas AA, Offermann N, et al. mTOR-dependent translation amplifies microglia priming in aging mice. J Clin Invest. 2021; 131(1).

[138] Wu M, Han J, Wu H, Liu Z. Proteasome-dependent senescent tumor cells mediate immunosuppression through CCL20 secretion and M2 polarization in pancreatic ductal adenocarcinoma. Front Immunol. 2023; 14: 1216376.

[139] Werneck-Gomes H, Campolina-Silva GH. Maria BT, Barata MC, Mahecha GAB, Hess RA, et al. Tumor-Associated Macrophages (TAM) are recruited to the aging prostate epithelial lesions and become intermingled with basal cells. Andrology. 2020; 8(5): 1375-86.

[140] Ghosh A, Michels J, Mezzadra R, Venkatesh D, Dong L, Gomez R, et al. Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade. J Clin Invest. 2022; 132(18).

[141] Guo Z, Wang G, Wu B, Chou WC, Cheng L, Zhou C, et al. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J Clin Invest. 2020; 130(11): 5893-908.

[142] Liu X, Si F, Bagley D, Ma F, Zhang Y, Tao Y, et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J Immunother Cancer. 2022; 10(10).

[143] Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, et al. TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy. Cell Metab. 2019; 29(1): 103-23.e5.

[144] Danileviciute E, Zeng N, Capelle CM, Paczia N, Gillespie MA, Kurniawan H, et al. PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T(reg) homeostasis during ageing. Nat Metab. 2022; 4(5): 589-607.

[145] Xu R, Wu M, Liu S, Shang W, Li R, Xu J, et al. Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4(+) Treg cells in ovarian cancer cells microenvironment. Cell Death Dis. 2021; 12(1): 22.

[146] Chang CY, You R, Armstrong D, Bandi A, Cheng YT, Burkhardt PM, et al. Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer. Sci Adv. 2022; 8(46): eabq0615.

[147] Park MJ, Baek JA, Choi JW, Jang SG, Kim DS, Park SH, et al. Programmed Death-Ligand 1 Expression Potentiates the Immune Modulatory Function Of Myeloid-Derived Suppressor Cells in Systemic Lupus Erythematosus. Front Immunol. 2021; 12: 606024.

[148] Saleh R, Toor SM, Taha RZ, Al-Ali D. Sasidharan Nair V, Elkord E. DNA methylation in the promoters of PD-L1, MMP9, ARG1, galectin-9, TIM-3, VISTA and TGF-β genes in HLA-DR(-) myeloid cells, compared with HLA-DR(+) antigen-presenting cells. Epigenetics. 2020; 15(12): 1275-88.

[149] Salminen A, Kaarniranta K, Kauppinen A. Phytochemicals inhibit the immunosuppressive functions of myeloid-derived suppressor cells (MDSC): Impact on cancer and age-related chronic inflammatory disorders. Int Immunopharmacol. 2018; 61: 231-40.

[150] Salminen A, Kaarniranta K, Kauppinen A. The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process. Ageing Res Rev. 2018; 48: 1-10.

[151] Salminen A, Kauppinen A, Kaarniranta K. Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Biogerontology. 2018; 19(5): 325-39.

[152] Chen X, Wang Y, Wang J, Wen J, Jia X, Wang X, et al. Accumulation of T-helper 22 cells, interleukin-22 and myeloid-derived suppressor cells promotes gastric cancer progression in elderly patients. Oncol Lett. 2018; 16(1): 253-61.

[153] Salminen A, Kauppinen A, Kaarniranta K. AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging. J Mol Med (Berl). 2019; 97(8): 1049-64.

[154] Okuma A, Hanyu A, Watanabe S, Hara E. p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. Nat Commun. 2017; 8(1): 2050.

[155] Lin Y, Cai Q, Chen Y, Shi T, Liu W, Mao L, et al. CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology. 2022; 75(1): 28-42.

[156] Que H, Fu Q, Lan T, Tian X, Wei X. Tumor-associated neutrophils and neutrophil-targeted cancer therapies. Biochim Biophys Acta Rev Cancer. 2022; 1877(5): 188762.

[157] Tsai HC, Tong ZJ, Hwang TL, Wei KC, Chen PY, Huang CY, et al. Acrolein produced by glioma cells under hypoxia inhibits neutrophil AKT activity and suppresses anti-tumoral activities. Free Radic Biol Med. 2023; 207: 17-28.

[158] Wang L, Liu Y, Dai Y, Tang X, Yin T, Wang C, et al. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. Gut. 2023; 72(5): 958-71.

[159] Seignez C, Martin A, Rollet CE, Racoeur C, Scagliarini A, Jeannin JF, et al. Senescence of tumor cells induced by oxaliplatin increases the efficiency of a lipid A immunotherapy via the recruitment of neutrophils. Oncotarget. 2014; 5(22): 11442-51.

[160] Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood. 2006; 107(12): 4817-24.

[161] Turinetto V, Vitale E, Giachino C. Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy. Int J Mol Sci. 2016; 17(7).

[162] Liu Y, Li L, Wu X, Qi H, Gao Y, Li Y, et al. MSC-AS1 induced cell growth and inflammatory mediators secretion through sponging miR-142-5p/DDX5 in gastric carcinoma. Aging (Albany NY). 2021; 13(7): 10387-95.

[163] Mojsilović S, Jauković A, Kukolj T, Obradović H, Okić Đorđević I, Petrović A, et al. Tumorigenic Aspects of MSC Senescence-Implication in Cancer Development and Therapy. J Pers Med. 2021; 11(11).

[164] Wang Q, Su X, Zhu R, Zhao RC. cAMP Agonist Forskolin Disrupts Mitochondrial Metabolism and Induces Senescence in Human Mesenchymal Cells. Stem Cells Dev. 2023; 32(3-4): 87-98.

[165] Cao YJ, Zheng YH, Li Q, Zheng J, Ma LT, Zhao CJ, et al. MSC Senescence-Related Genes Are Associated with Myeloma Prognosis and Lipid Metabolism-Mediated Resistance to Proteasome Inhibitors. J Oncol. 2022; 2022: 4705654.

[166] Zhang JM, Feng FE, Wang QM, Zhu XL, Fu HX, Xu LP, et al. Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression. Stem Cells Transl Med. 2016; 5(12): 1631-43.

[167] Zhu Y, Ge J, Huang C, Liu H, Jiang H. Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics. Theranostics. 2021; 11(12): 5675-85.

[168] Dorronsoro A, Santiago FE, Grassi D, Zhang T, Lai RC, McGowan SJ, et al. Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging. Aging Cell. 2021; 20(4): e13337.

[169] Li G, Zhang R, Zhang X, Shao S, Hu F, Feng Y. Human colorectal cancer derived-MSCs promote tumor cells escape from senescence via P53/P21 pathway. Clin Transl Oncol. 2020; 22(4): 503-11.

[170] Di Matteo S, Avanzini MA, Pelizzo G, Calcaterra V, Croce S, Spaggiari GM, et al. Neuroblastoma Tumor-Associated Mesenchymal Stromal Cells Regulate the Cytolytic Functions of NK Cells. Cancers (Basel). 2022; 15(1).

[171] Luo T, von der Ohe J, Hass R. MSC-Derived Extracellular Vesicles in Tumors and Therapy. Cancers (Basel). 2021; 13(20).

[172] Hendrayani SF, Al-Khalaf HH. Aboussekhra A. Curcumin triggers p16-dependent senescence in active breast cancer-associated fibroblasts and suppresses their paracrine procarcinogenic effects. Neoplasia. 2013; 15(6): 631-40.

[173] Ren C, Cheng X, Lu B, Yang G. Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment. Eur J Cancer. 2013; 49(18): 3889-99.

[174] Kim EK, Moon S, Kim DK, Zhang X, Kim J. CXCL1 induces senescence of cancer-associated fibroblasts via autocrine loops in oral squamous cell carcinoma. PLoS One. 2018; 13(1): e0188847.

[175] Wang T, Notta F, Navab R, Joseph J, Ibrahimov E, Xu J, et al. Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes. Mol Cancer Res. 2017; 15(1): 3-14.

[176] Hassona Y, Cirillo N, Heesom K, Parkinson EK, Prime SS. Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion. Br J Cancer. 2014; 111(6): 1230-7.

[177] Li H, Qiu L, Liu Q, Ma Z, Xie X, Luo Y, et al. Senescent Fibroblasts Generate a CAF Phenotype through the Stat3 Pathway. Genes (Basel). 2022; 13(9).

[178] Domingo-Vidal M, Whitaker-Menezes D. Martos-Rus C, Tassone P, Snyder CM, Tuluc M, et al. Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma. Mol Cancer Res. 2019; 17(9): 1893-909.

[179] Zhang J, Fu L, Yasuda-Yoshihara N. Yonemura A, Wei F, Bu L, et al. IL-1β derived from mixed-polarized macrophages activates fibroblasts and synergistically forms a cancer-promoting microenvironment. Gastric Cancer. 2023; 26(2): 187-202.

[180] Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014; 14(6): 430-9.

[181] Xu F, Huang M, Chen Q, Niu Y, Hu Y, Hu P, et al. LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway. Cancer Res. 2021; 81(22): 5678-91.

[182] Fu Y, Wang D, Wang H, Cai M, Li C, Zhang X, et al. TSPO deficiency induces mitochondrial dysfunction, leading to hypoxia, angiogenesis, and a growth-promoting metabolic shift toward glycolysis in glioblastoma. Neuro Oncol. 2020; 22(2): 240-52.

[183] Igelmann S, Lessard F, Uchenunu O, Bouchard J, Fernandez-Ruiz A. Rowell MC, et al. A hydride transfer complex reprograms NAD metabolism and bypasses senescence. Mol Cell. 2021; 81(18): 3848-65.e19.

[184] Meng SS, Gu HW, Zhang T, Li YS, Tang HB. Gradual deterioration of fatty liver disease to liver cancer via inhibition of AMPK signaling pathways involved in energy-dependent disorders, cellular aging, and chronic inflammation. Front Oncol. 2023; 13: 1099624.

[185] Chen J, Chen J, Huang J, Li Z, Gong Y, Zou B, et al. HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Aging (Albany NY). 2019; 11(23): 10839-60.

[186] Li Y, Lu Y, Lin SH, Li N, Han Y, Huang Q, et al. Insulin signaling establishes a developmental trajectory of adipose regulatory T cells. Nat Immunol. 2021; 22(9): 1175-85.

[187] Frediani E, Scavone F, Laurenzana A, Chillà A, Tortora K, Cimmino I, et al. Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence. J Cell Mol Med. 2022; 26(8): 2337-50.

[188] Oubaha M, Miloudi K, Dejda A, Guber V, Mawambo G, Germain MA, et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med. 2016; 8(362): 362ra144.

[189] van Vliet T, Varela-Eirin M. Wang B, Borghesan M, Brandenburg SM, Franzin R, et al. Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression. Mol Cell. 2021; 81(9): 2041-52.e6.

[190] Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420(6917): 860-7.

[191] Ying L, Yao Y, Lv H, Lu G, Zhang Q, Yang Y, et al. IL-17A contributes to skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway. Am J Physiol Cell Physiol. 2022; 322(5): C814-c24.

[192] Roy S, Kumaravel S, Banerjee P, White TK, O’Brien A, Seelig C, et al. Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma. Cells. 2021; 10(11).

[193] Woo Y, Kim H, Kim KC, Han JA, Jung YJ. Tumor-secreted factors induce IL-1β maturation via the glucose-mediated synergistic axis of mTOR and NF-κB pathways in mouse macrophages. PLoS One. 2018; 13(12): e0209653.

[194] Vaughan RA, Garcia-Smith R. Dorsey J, Griffith JK, Bisoffi M, Trujillo KA. Tumor necrosis factor alpha induces Warburg-like metabolism and is reversed by anti-inflammatory curcumin in breast epithelial cells. Int J Cancer. 2013; 133(10): 2504-10.

[195] Rohena-Rivera K, Sánchez-Vázquez MM, Aponte-Colón DA, Forestier-Román IS, Quintero-Aguiló ME, Martínez-Ferrer M. IL-15 regulates migration, invasion, angiogenesis and genes associated with lipid metabolism and inflammation in prostate cancer. PLoS One. 2017; 12(4): e0172786.

[196] Güç E, Pollard JW. Redefining macrophage and neutrophil biology in the metastatic cascade. Immunity. 2021; 54(5): 885-902.

[197] Ortiz-Montero P, Londoño-Vallejo A, Vernot JP. 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(1): 17.

[198] Homann L, Rentschler M, Brenner E, Böhm K, Röcken M, Wieder T. IFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma. Cells. 2022; 11(9).

[199] Hwang HJ, Lee YR, Kang D, Lee HC, Seo HR, Ryu JK, et al. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett. 2020; 490: 100-10.

[200] Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, et al. Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination. Cell Rep. 2021; 34(8): 108779.

[201] Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015; 17(8): 1049-61.

[202] Tominaga K, Suzuki HI. TGF-β Signaling in Cellular Senescence and Aging-Related Pathology. Int J Mol Sci. 2019; 20(20).

[203] Matsuda S, Revandkar A, Dubash TD, Ravi A, Wittner BS, Lin M, et al. TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state. Cell Rep. 2023; 42(3): 112129.

[204] Csermely P, Hódsági J, Korcsmáros T, Módos D, Perez-Lopez Á R, Szalay K, et al. Cancer stem cells display extremely large evolvability: alternating plastic and rigid networks as a potential Mechanism: network models, novel therapeutic target strategies, and the contributions of hypoxia, inflammation and cellular senescence. Semin Cancer Biol. 2015; 30: 42-51.

[205] Milanovic M, Fan DNY, Belenki D, Däbritz JHM, Zhao Z, Yu Y, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018; 553(7686): 96-100.

[206] Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008; 133(6): 1019-31.

[207] Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF, et al. Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis. Cancer Res. 2016; 76(4): 818-30.

[208] Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009; 15(6): 501-13.

[209] Otero-Albiol D, Carnero A. Cellular senescence or stemness: hypoxia flips the coin. J Exp Clin Cancer Res. 2021; 40(1): 243.

[210] Lee SH, Lee JH, Yoo SY, Hur J, Kim HS, Kwon SM. Hypoxia inhibits cellular senescence to restore the therapeutic potential of old human endothelial progenitor cells via the hypoxia-inducible factor-1α-TWIST-p21 axis. Arterioscler Thromb Vasc Biol. 2013; 33(10): 2407-14.

[211] Fiorillo M, Lamb R, Tanowitz HB, Cappello AR, Martinez-Outschoorn UE. Sotgia F, et al. Bedaquiline, an FDA-approve. antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). Aging (Albany NY). 2016; 8(8): 1593-607.

[212] Capparelli C, Whitaker-Menezes D. Guido C, Balliet R, Pestell TG, Howell A, et al. CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle. 2012; 11(12): 2272-84.

[213] Lambert AW, Pattabiraman DR, Weinberg RA. Emerging Biological Principles of Metastasis. Cell. 2017; 168(4): 670-91.

[214] Cai L, Xu S, Piao C, Qiu S, Li H, Du J. Adiponectin induces CXCL1 secretion from cancer cells and promotes tumor angiogenesis by inducing stromal fibroblast senescence. Mol Carcinog. 2016; 55(11): 1796-806.

[215] Shi Y, Liu Z, Zhang Q, Vallee I, Mo Z, Kishi S, et al. Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis. PLoS Biol. 2020; 18(12): e3000991.

[216] Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019; 18(1): 163.

[217] Jin F, Zheng X, Yang Y, Yao G, Ye L, Doeppner TR, et al. Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNFα and angiogenic VEGF. Aging (Albany NY). 2019; 11(2): 328-49.

[218] Gu J, Wang S, Guo H, Tan Y, Liang Y, Feng A, et al. Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis. Cell Death Dis. 2018; 9(2): 82.

[219] Yi L, Fan X, Li J, Yuan F, Zhao J, Nistér M, et al. Enrichment of branched chain amino acid transaminase 1 correlates with multiple biological processes and contributes to poor survival of IDH1 wild-type gliomas. Aging (Albany NY). 2021; 13(3): 3645-60.

[220] Zhang L, Liu M, Liu W, Hu C, Li H, Deng J, et al. Th17/IL-17 induces endothelial cell senescence via activation of NF-κB/p53/Rb signaling pathway. Lab Invest. 2021; 101(11): 1418-26.

[221] Zhao L, Li AQ, Zhou TF, Zhang MQ, Qin XM. Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. Am J Physiol Cell Physiol. 2014; 307(12): C1130-41.

[222] Molet S, Furukawa K, Maghazechi A, Hamid Q, Giaid A. Chemokine-and cytokine-induced expression of endothelin 1 and endothelin-converting enzyme 1 in endothelial cells. J Allergy Clin Immunol. 2000; 105(2 Pt 1): 333-8.

[223] Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C. Marini FC. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016; 18(1): 84.

[224] Feng C, Wu Z, Guo T, Jiang H, Guan M, Zhang Y, et al. BLCA-4 expression is related to MMP-9, VEGF, IL-1α and IL-8 in bladder cancer but not to PEDF, TNF-α or angiogenesis. Pathol Biol (Paris). 2012; 60(3): e36-40.

[225] Wang T, Li Y, Tuerhanjiang A, Wang W, Wu Z, Yuan M, et al. Correlation of Twist upregulation and senescence bypass during the progression and metastasis of cervical cancer. Front Med. 2014; 8(1): 106-12.

[226] Ma C, Wang F, Han B, Zhong X, Si F, Ye J, et al. SALL1 functions as a tumor suppressor in breast cancer by regulating cancer cell senescence and metastasis through the NuRD complex. Mol Cancer. 2018; 17(1): 78.

[227] Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH, 3rd, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016; 532(7598): 250-4.

[228] Feng D, Li D, Shi X, Xiong Q, Zhang F, Wei Q, et al. A gene prognostic index from cellular senescence predicting metastasis and radioresistance for prostate cancer. J Transl Med. 2022; 20(1): 252.

[229] Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell. 2006; 127(4): 679-95.

[230] Faheem MM, Seligson ND, Ahmad SM, Rasool RU, Gandhi SG, Bhagat M, et al. Convergence of therapy-induced senescence (TIS) and EMT in multistep carcinogenesis: current opinions and emerging perspectives. Cell Death Discov. 2020; 6: 51.

[231] Watanabe Y, Lee SW, Detmar M, Ajioka I, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells. Oncogene. 1997; 14(17): 2025-32.

[232] Brahimi-Horn MC, Giuliano S, Saland E, Lacas-Gervais S. Sheiko T, Pelletier J, et al. Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation. Cancer Metab. 2015; 3: 8.

[233] Rezaeian AH, Li CF, Wu CY, Zhang X, Delacerda J, You MJ, et al. A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis. Nat Cell Biol. 2017; 19(1): 38-51.

[234] Yasuda T, Ishimoto T, Baba H. Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche. Regen Ther. 2021; 17: 8-12.

[235] Feng Y, Liu J, Guo W, Guan Y, Xu H, Guo Q, et al. Atg7 inhibits Warburg effect by suppressing PKM2 phosphorylation resulting reduced epithelial-mesenchymal transition. Int J Biol Sci. 2018; 14(7): 775-83.

[236] Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, et al. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics. 2020; 10(15): 6928-45.

[237] Dodson M, Darley-Usmar V. Zhang J. Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med. 2013; 63: 207-21.

[238] Hou J, Yun Y, Xue J, Sun M, Kim S. D galactose induces astrocytic aging and contributes to astrocytoma progression and chemoresistance via cellular senescence. Mol Med Rep. 2019; 20(5): 4111-8.

[239] Jiang W, Ou Z, Zhu Q, Zai H. RagC GTPase regulates mTOR to promote chemoresistance in senescence-like HepG2 cells. Front Physiol. 2022; 13: 949737.

[240] Sullivan R, Paré GC, Frederiksen LJ, Semenza GL, Graham CH. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther. 2008; 7(7): 1961-73.

[241] Lucarelli G, Rutigliano M, Sallustio F, Ribatti D, Giglio A, Lepore Signorile M, et al. Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma. Aging (Albany NY). 2018; 10(12): 3957-85.

[242] Lisanti MP, Martinez-Outschoorn UE. Lin Z, Pavlides S, Whitaker-Menezes D. Pestell RG, et al. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs “fertilizer”. Cell Cycle. 2011; 10(15): 2440-9.

[243] Jakhar R, Luijten MNH, Wong AXF, Cheng B, Guo K, Neo SP, et al. Autophagy Governs Protumorigenic Effects of Mitotic Slippage-induced Senescence. Mol Cancer Res. 2018; 16(11): 1625-40.

[244] Espinoza I, Yang L, Steen TV, Vellon L, Cuyàs E, Verdura S, et al. Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α(6)β(1) drives endocrine resistance in breast cancer cells. Aging (Albany NY). 2022; 14(3): 1200-13.

[245] Özeş AR, Miller DF, Özeş ON, Fang F, Liu Y, Matei D, et al. NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 2016; 35(41): 5350-61.

[246] Nacarelli T, Fukumoto T, Zundell JA, Fatkhutdinov N, Jean S, Cadungog MG, et al. NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer. Cancer Res. 2020; 80(4): 890-900.

[247] Fletcher-Sananikone E, Kanji S, Tomimatsu N, Di Cristofaro LFM, Kollipara RK, Saha D, et al. Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence. Cancer Res. 2021; 81(23): 5935-47.

[248] McCaul JA, Gordon KE, Minty F, Fleming J, Parkinson EK. Telomere dysfunction is related to the intrinsic radio-resistance of human oral cancer cells. Oral Oncol. 2008; 44(3): 261-9.

[249] Schoetz U, Klein D, Hess J, Shnayien S, Spoerl S, Orth M, et al. Early senescence and production of senescence-associated cytokines are major determinants of radioresistance in head-and-neck squamous cell carcinoma. Cell Death Dis. 2021; 12(12): 1162.

[250] Yu X, Liu Y, Yin L, Peng Y, Peng Y, Gao Y, et al. Radiation-promoted CDC6 protein stability contributes to radioresistance by regulating senescence and epithelial to mesenchymal transition. Oncogene. 2019; 38(4): 549-63.

[251] Lee M, Nam HY, Kang HB, Lee WH, Lee GH, Sung GJ, et al. Epigenetic regulation of p62/SQSTM1 overcomes the radioresistance of head and neck cancer cells via autophagy-dependent senescence induction. Cell Death Dis. 2021; 12(3): 250.

[252] Chaturvedi P, George V, Shrestha N, Wang M, Dee MJ, Zhu X, et al. Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells. Mol Ther. 2022; 30(3): 1171-87.

[253] Ewald JA, Desotelle JA, Wilding G, Jarrard DF. Therapy-induced senescence in cancer. J Natl Cancer Inst. 2010; 102(20): 1536-46.

[254] Sidi R, Pasello G, Opitz I, Soltermann A, Tutic M, Rehrauer H, et al. Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis. Eur J Cancer. 2011; 47(2): 326-32.

[255] Schmitt CA, Wang B, Demaria M. Senescence and cancer -role and therapeutic opportunities. Nat Rev Clin Oncol. 2022; 19(10): 619-36.

[256] Wang B, Kohli J, Demaria M. Senescent Cells in Cancer Therapy: Friends or Foes? Trends Cancer. 2020; 6(10): 838-57.

[257] Takasugi M, Yoshida Y, Hara E, Ohtani N. The role of cellular senescence and SASP in tumour microenvironment. Febs j. 2023; 290(5): 1348-61.

[258] Nelson G, Kucheryavenko O, Wordsworth J, von Zglinicki T. The senescent bystander effect is caused by ROS-activated NF-κB signalling. Mech Ageing Dev. 2018; 170: 30-6.

[259] Hubackova S, Krejcikova K, Bartek J, Hodny Z. IL1-and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induce. paracrine ‘bystander senescence’. Aging (Albany NY). 2012; 4(12): 932-51.

[260] Poillet-Perez L, White E. Role of tumor and host autophagy in cancer metabolism. Genes Dev. 2019; 33(11-12): 610-9.

[261] Kaushik S, Tasset I, Arias E, Pampliega O, Wong E, Martinez-Vicente M. et al. Autophagy and the hallmarks of aging. Ageing Res Rev. 2021; 72: 101468.

[262] Hupfer A, Brichkina A, Koeniger A, Keber C, Denkert C, Pfefferle P, et al. Matrix stiffness drives stromal autophagy and promotes formation of a protumorigenic niche. Proc Natl Acad Sci U S A. 2021; 118(40).

[263] Carleton G, Lum JJ. Autophagy metabolically suppresses CD8(+) T cell antitumor immunity. Autophagy. 2019; 15(9): 1648-9.

[264] Kimmelman AC, White E. Autophagy and Tumor Metabolism. Cell Metab. 2017; 25(5): 1037-43.

[265] Huang Z, Gan S, Zhuang X, Chen Y, Lu L, Wang Y, et al. Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy. Cells. 2022; 11(16).

[266] Fang J, Chen Z, Lai X, Yin W, Guo Y, Zhang W, et al. Mesenchymal stem cells-derived HIF-1α-overexpressed extracellular vesicles ameliorate hypoxia-induced pancreatic β cell apoptosis and senescence through activating YTHDF1-mediated protective autophagy. Bioorg Chem. 2022; 129: 106194.

[267] Zhang L, Wang X, Yu W, Ying J, Fang P, Zheng Q, et al. CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD. Front Immunol. 2022; 13: 836494.

[268] Sharif T, Martell E, Dai C, Kennedy BE, Murphy P, Clements DR, et al. Autophagic homeostasis is required for the pluripotency of cancer stem cells. Autophagy. 2017; 13(2): 264-84.

[269] Wu J, Zhao X, Sun Q, Jiang Y, Zhang W, Luo J, et al. Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model. Biomed Pharmacother. 2020; 125: 109746.

[270] Marcucci F, Ghezzi P, Rumio C. The role of autophagy in the cross-talk between epithelial-mesenchymal transitioned tumor cells and cancer stem-like cells. Mol Cancer. 2017; 16(1): 3.

[271] Biddle A, Gammon L, Liang X, Costea DE, Mackenzie IC. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine. 2016; 4: 138-45.

[272] Liang L, Hui K, Hu C, Wen Y, Yang S, Zhu P, et al. Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells. J Exp Clin Cancer Res. 2019; 38(1): 71.

[273] Li H, Li J, Chen L, Qi S, Yu S, Weng Z, et al. HERC3-Mediated SMAD7 Ubiquitination Degradation Promotes Autophagy-Induced EMT and Chemoresistance in Glioblastoma. Clin Cancer Res. 2019; 25(12): 3602-16.

[274] Liu Z, Wang Z, Chen D, Liu X, Yu G, Zhang Y, et al. Paeoniflorin Inhibits EMT and Angiogenesis in Human Glioblastoma via K63-Linked C-Met Polyubiquitination-Dependent Autophagic Degradation. Front Oncol. 2022; 12: 785345.

[275] Amiama-Roig A, Verdugo-Sivianes EM. Carnero A, Blanco JR. Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy. Cancers (Basel). 2022; 14(20).

[276] Jung-Hynes B, Reiter RJ, Ahmad N. Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res. 2010; 48(1): 9-19.

[277] Wu J, Bu D, Wang H, Shen D, Chong D, Zhang T, et al. The rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice. Nat Commun. 2023; 14(1): 1634.

[278] Blacher E, Tsai C, Litichevskiy L, Shipony Z, Iweka CA, Schneider KM, et al. Aging disrupts circadian gene regulation and function in macrophages. Nat Immunol. 2022; 23(2): 229-36.

[279] Wang C, Barnoud C, Cenerenti M, Sun M, Caffa I, Kizil B, et al. Dendritic cells direct circadian anti-tumour immune responses. Nature. 2023; 614(7946): 136-43.

[280] Wu J, Jing X, Du Q, Sun X, Holgersson K, Gao J, et al. Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-β-myoCAF-Dependent Mechanism. Adv Sci (Weinh). 2023:e2301505.

[281] García-Costela M, Escudero-Feliú J, Puentes-Pardo JD. San Juán SM, Morales-Santana S. Ríos-Arrabal S, et al. Circadian Genes as Therapeutic Targets in Pancreatic Cancer. Front Endocrinol (Lausanne). 2020; 11: 638.

[282] Wang CY, Wen MS, Wang HW, Hsieh IC, Li Y, Liu PY, et al. Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2. Circulation. 2008; 118(21): 2166-73.

[283] Toledo M, Batista-Gonzalez A. Merheb E, Aoun ML, Tarabra E, Feng D, et al. Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1. Cell Metab. 2018; 28(2): 268-81.e4.

[284] Afshar K, Sanaei MJ, Ravari MS, Pourbagheri-Sigaroodi A. Bashash D. An overview of extracellular matrix and its remodeling in the development of cancer and metastasis with a glance at therapeutic approaches. Cell Biochem Funct. 2023; 41(8): 930-52.

[285] Panwar P, Lamour G, Mackenzie NC, Yang H, Ko F, Li H, et al. Changes in Structural-Mechanical Properties and Degradability of Collagen during Aging-associated Modifications. J Biol Chem. 2015; 290(38): 23291-306.

[286] Kaur A, Ecker BL, Douglass SM, Kugel CH, 3rd, Webster MR, Almeida FV, et al. Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov. 2019; 9(1): 64-81.

[287] Naba A, Clauser KR, Hoersch S, Liu H, Carr SA, Hynes RO. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol Cell Proteomics. 2012; 11(4): M111.014647.

[288] Northey JJ, Przybyla L, Weaver VM. Tissue Force Programs Cell Fate and Tumor Aggression. Cancer Discov. 2017; 7(11): 1224-37.

[289] Mavrogonatou E, Pratsinis H, Papadopoulou A, Karamanos NK, Kletsas D. Extracellular matrix alterations in senescent cells and their significance in tissue homeostasis. Matrix Biol. 2019; 75-76: 27-42.

[290] Burgstaller G, Oehrle B, Gerckens M, White ES, Schiller HB, Eickelberg O. The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease. Eur Respir J. 2017; 50(1).

[291] Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011; 17(3): 320-9.

[292] Dituri F, Mazzocca A, Giannelli G, Antonaci S. PI3K functions in cancer progression, anticancer immunity and immune evasion by tumors. Clin Dev Immunol. 2011; 2011: 947858.

[293] Nicolas-Boluda A, Vaquero J, Vimeux L, Guilbert T, Barrin S, Kantari-Mimoun C. et al. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment. Elife. 2021; 10.

[294] Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017; 65(10): 2297-301.

[295] Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020; 288(5): 518-36.

[296] Yosef R, Pilpel N, Tokarsky-Amiel R. Biran A, Ovadya Y, Cohen S, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016; 7: 11190.

[297] Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016; 22(1): 78-83.

[298] Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015; 14(4): 644-58.

[299] Wang L, Leite de Oliveira R, Wang C, Fernandes Neto JM, Mainardi S, Evers B, et al. High-Throughput Functional Genetic and Compound Screens Identify Targets for Senescence Induction in Cancer. Cell Rep. 2017; 21(3): 773-83.

[300] Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, et al. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife. 2017; 6.

[301] Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011; 479(7374): 547-51.

[302] Ruscetti M, Morris JPt, Mezzadra R, Russell J, Leibold J, Romesser PB, et al. Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer. Cell. 2020; 181(2): 424-41.e21.

[303] Pereira BI, Devine OP, Vukmanovic-Stejic M. Chambers ES, Subramanian P, Patel N, et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition. Nat Commun. 2019; 10(1): 2387.

[304] Moiseeva O, Deschênes-Simard X, St-Germain E. Igelmann S, Huot G, Cadar AE, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013; 12(3): 489-98.

[305] Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Natl Acad Sci U S A. 2009; 106(40): 17031-6.

[306] Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A, Trotman LC, et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest. 2010; 120(3): 681-93.

[307] Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021; 398(10304): 1002-14.

[308] Sceneay J, Goreczny GJ, Wilson K, Morrow S, DeCristo MJ, Ubellacker JM, et al. Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer. Cancer Discov. 2019; 9(9): 1208-27.

[309] Lages CS, Lewkowich I, Sproles A, Wills-Karp M. Chougnet C. Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway. Aging Cell. 2010; 9(5): 785-98.

[310] Ikeda K, Horie-Inoue K. Suzuki T, Hobo R, Nakasato N, Takeda S, et al. Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance. Nat Commun. 2019; 10(1): 4108.

[311] Saleh T, Carpenter VJ, Tyutyunyk-Massey L. Murray G, Leverson JD, Souers AJ, et al. Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-X(L) -BAX interaction. Mol Oncol. 2020; 14(10): 2504-19.

[312] Martell E, Kuzmychova H, Senthil H, Kaul E, Chokshi CR, Venugopal C, et al. Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations. Acta Neuropathol Commun. 2023; 11(1): 110.

[313] Lozano-Torres B, Galiana I, Rovira M, Garrido E, Chaib S, Bernardos A, et al. An OFF-ON Two-Photon Fluorescent Probe for Tracking Cell Senescence in Vivo. J Am Chem Soc. 2017; 139(26): 8808-11.

[314] Dolgin E. Send in the senolytics. Nat Biotechnol. 2020; 38(12): 1371-7.

[315] Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020; 583(7814): 127-32.

[316] Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY). 2017; 9(8): 1867-84.

[317] Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010; 24(22): 2463-79.

[318] Dominic A, Banerjee P, Hamilton DJ, Le NT, Abe JI. Time-dependent replicative senescence vs. disturbed flow-induced pre-mature aging in atherosclerosis. Redox Biol. 2020; 37: 101614.

[319] Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023; 8(1): 239.

[320] Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017; 7(2): 165-76.

[321] Grosse L, Wagner N, Emelyanov A, Molina C, Lacas-Gervais S. Wagner KD, et al. Defined p16(High) Senescent Cell Types Are Indispensable for Mouse Healthspan. Cell Metab. 2020; 32(1): 87-99.e6.

[322] Jain S, Rick JW, Joshi RS, Beniwal A, Spatz J, Gill S, et al. Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects. J Clin Invest. 2023; 133(5).

[323] Moncada R, Barkley D, Wagner F, Chiodin M, Devlin JC, Baron M, et al. Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas. Nat Biotechnol. 2020; 38(3): 333-42.

[324] Luo X, Fu Y, Loza AJ, Murali B, Leahy KM, Ruhland MK, et al. Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development. Cell Rep. 2016; 14(1): 82-92.

[325] Liu D, Hornsby PJ. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 2007; 67(7): 3117-26.

[326] Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, et al. Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE(2)-Mediated Suppression of Antitumor Immunity. Cancer Discov. 2017; 7(5): 522-38.

[327] Bent EH, Gilbert LA, Hemann MT. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016; 30(16): 1811-21.

[328] Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016; 7: 11762.

[329] Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445(7128): 656-60.

[330] Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 2014; 9(1): 75-89.

[331] Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature. 2014; 515(7525): 134-7.

[332] Kim YH, Choi YW, Lee J, Soh EY, Kim JH, Park TJ. Senescent tumor cells lead the collective invasion in thyroid cancer. Nat Commun. 2017; 8: 15208.

[333] Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013; 15(8): 978-90.

[334] 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. 2019; 39(12).

[335] Gayle SS, Sahni JM, Webb BM, Weber-Bonk KL. Shively MS, Spina R, et al. Targeting BCL-xL improves the efficacy of bromodomain and extra-terminal protein inhibitors in triple-negative breast cancer by eliciting the death of senescent cells. J Biol Chem. 2019; 294(3): 875-86.

[336] Hao X, Zhao B, Zhou W, Liu H, Fukumoto T, Gabrilovich D, et al. Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype. iScience. 2021; 24(1): 102016.

[337] Hu Q, Peng J, Jiang L, Li W, Su Q, Zhang J, 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. 2020; 11(10): 925.

[338] Wang C, Vegna S, Jin H, Benedict B, Lieftink C, Ramirez C, et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature. 2019; 574(7777): 268-72.

[339] Niklander S, Bandaru D, Lambert DW, Hunter KD. ROCK inhibition modulates the senescence-associated secretory phenotype (SASP) in oral keratinocytes. FEBS Open Bio. 2020; 10(12): 2740-9.

[340] Alimbetov D, Davis T, Brook AJ, Cox LS, Faragher RG, Nurgozhin T, et al. Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology. 2016; 17(2): 305-15.

[341] Lim H, Park H, Kim HP. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem Pharmacol. 2015; 96(4): 337-48.

[342] Laberge RM, Zhou L, Sarantos MR, Rodier F, Freund A, de Keizer PL, et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell. 2012; 11(4): 569-78.

[343] Rudolph J, Heine A, Quast T, Kolanus W, Trebicka J, Brossart P, et al. The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. Leukemia. 2016; 30(10): 2119-23.

[344] Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X(L) inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017; 9(3): 955-63.

[345] Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 2016; 8(11): 2915-26.

RIGHTS & PERMISSIONS

2024 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.