Formation mechanism of senescent microenvironment after glioblastoma radiotherapy and research progress on targeted strategies

doi:10.3760/cma.j.cn371439-20251031-00078

Abstract

Abstract:

Glioblastoma is the most malignant primary brain tumor， and patients often experience poor prognosis due to radiotherapy resistance and tumor recurrence following standard chemoradiotherapy. Recent studies have revealed that radiotherapy not only kills tumor cells but also induces cellular senescence in tumor cells and surrounding astrocytes， endothelial cells， etc.， thereby forming a senescent microenvironment that promotes tumor progression. Senescent cells secrete a variety of cytokines via the senescence-associated secretory phenotype， which remodels the immune and vascular microenvironments， facilitating tumor regeneration and treatment resistance. Regarding these mechanisms， the senescent cell clearance agents and senescence phenotype inhibitors have demonstrated significant tumor-suppressive effects in preclinical studies. A systematic discussion on the formation mechanisms of the senescent microenvironment and its role in radiotherapy resistance in glioblastoma， as well as the summary and outlook of therapeutic strategies targeting this microenvironment， can provide new research directions for reducing the risk of tumor recurrence.

Key words: Glioblastoma, Cellular senescence, Tumor microenvironment, Radiation tolerance

Gao Jian, Zhu Wei. Formation mechanism of senescent microenvironment after glioblastoma radiotherapy and research progress on targeted strategies[J]. Journal of International Oncology, 2026, 53(8): 485-490.

Figures/Tables 2

References 49

[1]	Singh S, Dey D, Barik D, et al. Glioblastoma at the crossroads: current understanding and future therapeutic horizons[J]. Signal Transduct Target Ther, 2025, 10(1): 213. DOI: 10.1038/s41392-025-02299-4.
[2]	付海韬, 刘幸, 刘玉清. 神经胶质母细胞瘤与其微环境相互作用的研究进展[J]. 解剖学报, 2025, 56(1): 66-73. DOI: 10.16098/j.issn.0529-1356.2025.01.009.
[3]	Bhuvanalakshmi G, Gamit N, Patil M, et al. Stemness, pluripoten-tiality, and wnt antagonism: sFRP4, a Wnt antagonist mediates pluripo-tency and stemness in glioblastoma[J]. Cancers (Basel), 2018, 11(1): 25. DOI: 10.3390/cancers11010025.
[4]	Ji JX, Ding KK, Cheng B, et al. Radiotherapy-induced astrocyte senescence promotes an immunosuppressive microenvironment in glioblastoma to facilitate tumor regrowth[J]. Adv Sci (Weinh), 2024, 11(15): e2304609. DOI: 10.1002/advs.202304609.
[5]	Fletcher-sananikone E, Kanji S, Tomimatsu N, et al. Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence[J]. Cancer Res, 2021, 81(23): 5935-5947. DOI: 10.1158/0008-5472.CAN-21-0752. pmid: 34580063
[6]	曾女金, 邢孟韬, 何玲. 治疗诱导性衰老在胶质母细胞瘤中的研究进展[J]. 中南药学, 2023, 21(5): 1329-1334.
[7]	Demaria M, O'leary MN, Chang JH, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse[J]. Cancer Discov, 2017, 7(2): 165-176. DOI: 10.1158/2159-8290.CD-16-0241. pmid: 27979832
[8]	Spina A, De Pasquale V, Cerulo G, et al. HGF/c-MET axis in tumor microenvironment and metastasis formation[J]. Biomedicines, 2015, 3(1): 71-88. DOI: 10.3390/biomedicines3010071. pmid: 28536400
[9]	Sultana P, Honc O, Hodny Z, et al. Clusterin deficiency promotes cellular senescence in human astrocytes[J]. Mol Neurobiol, 2025, 62(5): 5774-5786. DOI: 10.1007/s12035-024-04650-2.
[10]	Liu YF, Yang M, Luo JJ, et al. Radiotherapy targeting cancer stem cells "awakens" them to induce tumour relapse and metastasis in oral cancer[J]. Int J Oral Sci, 2020, 12(1): 19. DOI: 10.1038/s41368-020-00087-0.
[11]	Li Q, Wang CD, Cai L, et al. MiR-34a derived from mesenchymal stem cells stimulates senescence in glioma cells by inducing DNA damage[J]. Mol Med Rep, 2019, 19(3): 1849-1857. DOI: 10.3892/mmr.2018.9800.
[12]	De Magalhães JP. Cellular senescence in normal physiology[J]. Science, 2024, 384(6702): 1300-1301. DOI: 10.1126/science.adj7050. pmid: 38900869
[13]	Chojak R, Fares J, Petrosyan E, et al. Cellular senescence in glioma[J]. J Neuro-oncol, 2023, 164(1): 11-29. DOI: 10.1007/s11060-023-04387-3. pmid: 37458855
[14]	Tomimatsu N, Di Cristofaro LFM, Kanji S, et al. Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy[J]. EMBO Mol Med, 2025, 17(4): 645-678. DOI: 10.1038/s44321-025-00201-x.
[15]	Coppé JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory phenotype: the dark side of tumor suppression[J]. Annu Rev Pathol, 2010, 5: 99-118. DOI: 10.1146/annurev-pathol-121808-102144.
[16]	Ghorai A, Singh B, Dutt S. Biphasic DNA damage and non-canonical replication stress response govern radiation-induced senescence in glioblastoma[J]. J Cell Sci, 2024, 137(24): jcs261844. DOI: 10.1242/jcs.261844.
[17]	Turnquist C, Beck JA, Horikawa I, et al. Radiation-induced astrocyte senescence is rescued by Δ133p53[J]. Neuro Oncol, 2019, 21(4): 474-485. DOI: 10.1093/neuonc/noz001.
[18]	Ruhland MK, Loza AJ, Capietto AH, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis[J]. Nat Commun, 2016, 7: 11762. DOI: 10.1038/ncomms11762. pmid: 27272654
[19]	Fares J, Fares MY, Khachfe HH, et al. Molecular principles of metastasis: a hallmark of cancer revisited[J]. Signal Transduct Target Ther, 2020, 5(1): 28. DOI: 10.1038/s41392-020-0134-x.
[20]	Liu Q, Bao HB, Zhang SB, et al. Identification of a cellular senescence-related-lncRNA (SRlncRNA) signature to predict the overall survival of glioma patients and the tumor immune micro-environment[J]. Front Genet, 2023, 14: 1096792. DOI: 10.3389/fgene.2023.1096792.
[21]	Hasan T, Caragher SP, Shireman JM, et al. Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumo-rigenicity in glioblastoma[J]. Cell Death Dis, 2019, 10(4): 292. DOI: 10.1038/s41419-019-1387-6.
[22]	Wang D, Hao XY, Jia LY, et al. Cellular senescence and abdominal aortic aneurysm: from pathogenesis to therapeutics[J]. Front Cardiovasc Med, 2022, 9: 999465. DOI: 10.3389/fcvm.2022.999465.
[23]	Park SS, Roh TH, Tanaka Y, et al. High p16^INK4A expression in glioblastoma is associated with senescence phenotype and better prognosis[J]. Neoplasia, 2025, 60: 101116. DOI: 10.1016/j.neo.2024.101116.
[24]	Carreno G, Guiho R, Martinez-barbera JP. Cell senescence in neuropathology: a focus on neurodegeneration and tumours[J]. Neuropathol Appl Neurobiol, 2021, 47(3): 359-378. DOI: 10.1111/nan.12689.
[25]	Johnson DE, O'keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer[J]. Nat Rev Clin Oncol, 2018, 15(4): 234-248. DOI: 10.1038/nrclinonc.2018.8. pmid: 29405201
[26]	Chatterjee D, Chakrabarti O. Role of stress granules in modulating senescence and promoting cancer progression: special emphasis on glioma[J]. Int J Cancer, 2022, 150(4): 551-561. DOI: 10.1002/ijc.33787.
[27]	Gorodezki D, Schuhmann MU, Ebinger M, et al. Dissecting the natural patterns of progression and Senescence in pediatric low-grade glioma: from cellular mechanisms to clinical implications[J]. Cells, 2024, 13(14): 1215. DOI: 10.3390/cells13141215.
[28]	杜启联, 胡钦勇. 单细胞视角下的肿瘤浸润免疫细胞[J]. 国际肿瘤学杂志, 2024, 51(7): 458-463. DOI: 10.3760/cma.j.cn371439-20231130-00075.
[29]	韩潞伟, 张弓. 放射治疗及免疫检查点抑制剂治疗胶质母细胞瘤的研究进展[J]. 中华实用诊断与治疗杂志, 2025, 39(1): 89-92. DOI: 10.13507/j.issn.1674-3474.2025.01.015.
[30]	Luo N, Zhu WJ, Li XY, et al. Defective autophagy of pericytes enhances radiation-induced senescence promoting radiation brain injury[J]. Neuro Oncol, 2024, 26(12): 2288-2304. DOI: 10.1093/neuonc/noae153.
[31]	Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer[J]. Nat Rev Cancer, 2022, 22(6): 340-355. DOI: 10.1038/s41568-022-00450-9. pmid: 35241831
[32]	Ordónez-rubiano EG, Cómbita A, Baldoncini M, et al. Cellular senescence in diffuse gliomas: from physiopathology to possible treatments[J]. World Neurosurg, 2024, 191: 138-148. DOI: 10.1016/j.wneu.2024.08.060. pmid: 39233309
[33]	Liu JQ, Xiao Q, Xiao JN, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities[J]. Signal Transduct Target Ther, 2022, 7(1): 3. DOI: 10.1038/s41392-021-00762-6.
[34]	岳红云, 张百红. 肿瘤的衰老治疗[J]. 国际肿瘤学杂志, 2023, 50(12): 734-738. DOI: 10.3760/cma.j.cn371439-20230606-00138.
[35]	Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation[J]. J Intern Med, 2020, 288(5): 518-536. DOI: 10.1111/joim.13141.
[36]	Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs[J]. Aging cell, 2015, 14(4): 644-658. DOI: 10.1111/acel.12344. pmid: 25754370
[37]	Ketkar M, Desai S, Rana P, et al. Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma[J]. Neuro Oncol, 2024, 26(11): 2027-2043. DOI: 10.1093/neuonc/noae134.
[38]	Chang JH, Wang YY, Shao LJ, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice[J]. Nat Med, 2016, 22(1): 78-83. DOI: 10.1038/nm.4010. pmid: 26657143
[39]	Jensen S, Seidelin JB, Lacasse EC, et al. SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases[J]. Sci Signal, 2020, 13(619): eaax8295. DOI: 10.1126/scisignal.aax8295.
[40]	Short S, Fielder E, Miwa S, et al. Senolytics and senostatics as adjuvant tumour therapy[J]. EBioMedicine, 2019, 41: 683-692. DOI: 10.1016/j.ebiom.2019.01.056. pmid: 30737084
[41]	Schmitt CA, Wang BS, Demaria M. Senescence and cancer-role and therapeutic opportunities[J]. Nat Rev Clin Oncol, 2022, 19(10): 619-636. DOI: 10.1038/s41571-022-00668-4.
[42]	Jane EP, Premkumar DR, Rajasundaram D, et al. Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases[J]. Mol Oncol, 2022, 16(1): 219-249. DOI: 10.1002/1878-0261.13025.
[43]	Zhang L, Pitcher LE, Yousefzadeh MJ, et al. Cellular senescence: a key therapeutic target in aging and diseases[J]. J Clin Invest, 2022, 132(15): e158450. DOI: 10.1172/JCI158450.
[44]	Prasanna PG, Citrin DE, Hildesheim J, et al. Therapy-induced senescence: opportunities to improve anticancer therapy[J]. J Natl Cancer Inst, 2021, 113(10): 1285-1298. DOI: 10.1093/jnci/djab064. pmid: 33792717
[45]	Beltzig L, Christmann M, Kaina B. Abrogation of cellular senescence induced by temozolomide in glioblastoma cells: search for senolytics[J]. Cells, 2022, 11(16): 2588. DOI: 10.3390/cells11162588.
[46]	Zhang C Neha, Zhang JQ, et al. Aging and senescence: key players in brain tumor progression and drug resistance[J]. Drug Resist Updat, 2025, 81: 101228. DOI: 10.1016/j.drup.2025.101228.
[47]	Rossi M, Abdelmohsen K. The emergence of senescent surface biomarkers as senotherapeutic targets[J]. Cells, 2021, 10(7): 1740. DOI: 10.3390/cells10071740.
[48]	Wang TW, Johmura Y, Suzuki N, et al. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes[J]. Nature, 2022, 611(7935): 358-364. DOI: 10.1038/s41586-022-05388-4.
[49]	Khan S, Zhang X, Lv DW, et al. A selective BCL-X_L PROTAC degrader achieves safe and potent antitumor activity[J]. Nat Med, 2019, 25(12): 1938-1947. DOI: 10.1038/s41591-019-0668-z.

细胞类型	主要衰老诱导信号通路	关键SASP因子	主要促瘤机制	介导治疗抵抗的机制
肿瘤细胞	p53-p21、 p16-Rb^[11]	IL-6、IL-8、 CXCL1^[14-15]	①旁分泌作用促进邻近肿瘤细胞增殖与侵袭； ②驱动“旁分泌衰老”，扩大衰老细胞群^[14-15]	通过激活JAK/STAT等信号通路上调抗凋亡蛋白，增强放疗抵抗^[14-15]
星形胶质细胞	p21^Cip1和 p16^INK4a[17]	HGF、 TNF-α^[18-19]	①通过HGF/c-Met轴增强肿瘤细胞迁移与侵袭^[18-19]；②招募髓系免疫抑制细胞，营造免疫抑制微环境^[18]	介导免疫逃逸，削弱放疗的远隔效应和免疫治疗的疗效^[18-19]
血管内皮细胞	p53-p21、 p16-Rb^[22-23]	CXCL5、 CXCL8（IL-8）^[21]	①通过CXCL5/CXCR2轴诱导肿瘤基因组不稳定性^[21]；②促进血管新生^[21]	为肿瘤进化提供演化优势，增加肿瘤异质性和适应性^[21]
免疫细胞（如小胶质细胞）	p16-Rb^[22-23]	TGF-β、 IL-10^[18,24]	极化为M2抑制表型，直接抑制T细胞功能^[18,24]	共同导致“冷肿瘤”表型，是免疫治疗抵抗的核心原因之一^[18,24]

策略类别	代表药物/方法	核心作用机制	优势	挑战/局限性	临床前/临床进展
衰老细胞清除剂（清除衰老细胞）	ABT-263 （navitoclax）^[5,38]	抑制BCL-2/BCL-xL，诱导线粒体凋亡^[35-37]	从根本上减少衰老细胞负荷，效果可能更持久^[35]	①血脑屏障穿透性^[35]；②血小板减少等血液学毒性^[35]	在GBM小鼠模型中可延缓复发，延长总生存期^[38]
	比瑞那帕（SMAC模拟物）^[39]	拮抗cIAP1/2，放疗后衰老细胞凋亡^[39]	放疗后清除衰老细胞，抑制SASP，防止复发^[39]	①血脑屏障暴露待证；②毒性与分层难^[39]	放疗后可延长GBM小鼠模型的生存期；暂无临床试验^[39]
衰老表型抑制剂（抑制SASP）	JAK抑制剂（如ruxolitinib）^[41]	抑制JAK/STAT信号通路，减少SASP因子产生^[40-41]	避免细胞死亡引发的炎症；可能引发的不良反应更小^[40]	①不减少衰老细胞数量；②需长期持续给药^[40]	在模型中可抑制SASP的促瘤效应^[7,41]
	NF-κB抑制剂^[14]	阻断NF-κB通路，从上游抑制SASP转录^[14]	靶向SASP的核心调控枢纽^[14,40]	特异性、全身性抑制的潜在毒性^[14,40]	多为临床前研究阶段^[14,40]
联合/时序策略	“一击二击” （放疗→衰老细胞清除剂）^[44-45]	先诱导衰老，再特异性清除^[44-45]	时序逻辑清晰，精准根除“复发种子”^[44-45]	治疗时间窗口的精准确定是挑战^[44-45]	临床前研究显示协同增效^[44-45]
	衰老细胞清除剂→免疫检查点抑制剂^[46]	先清除衰老细胞改善免疫微环境，再激活T细胞^[47-48]	有望将“冷肿瘤”转化为“热肿瘤”^[46-48]	最佳联合方案和时序有待优化^[46-48]	极具潜力的新范式，处于早期探索阶段^[46-48]