染色体不稳定性调控肿瘤免疫微环境：从基础机制到结直肠癌治疗突破
Chromosomal Instability Regulates the Tumor Immune Microenvironment: From Fundamental Mechanisms to Therapeutic Breakthroughs in Colorectal Cancer Treatment
摘要: 染色体不稳定性(Chromosomal instability, CIN)作为实体瘤的主要特征之一，通过驱动基因组异质性、微核形成及细胞质双链DNA (dsDNA)累积等多种复杂的机制对肿瘤免疫微环境(TME)的形成及其对免疫应答造成一定的影响。近年来研究揭示了CIN的“两面性”：即中等水平的CIN能使肿瘤更好地适应肿瘤微环境的变化，而过度的CIN会导致遗传灾难和细胞死亡，触发细胞焦亡并释放损伤相关分子模式(DAMPs)，提高抗肿瘤免疫识别。然而，CIN与免疫微环境之间的关系目前仍然是一个复杂的网络，特别是在结直肠癌(CRC)中，CIN相关分子机制(如YY2/BUB1B轴)通过释放肿瘤新抗原和促炎因子(IL-1、IFNγ)，重塑TME并克服微卫星稳定(MSS)型CRC的免疫治疗抵抗。此外，联合丝氨酸/苏氨酸激酶(AURK)抑制剂与免疫检查点阻断、或通过代谢重编程靶向糖酵解和DNA修复通路，为克服CRC治疗耐药提供了新策略。本文整合基础机制与临床转化视角，提出靶向CIN-TME交互网络的联合治疗策略，为优化结直肠癌免疫治疗及拓展适应症提供理论依据和应用前景。
Abstract: Chromosomal instability (CIN), as one of the main features of solid tumors, affects the formation of tumor immune microenvironment (TME) and its impact on immune response through various complex mechanisms, such as driving genomic heterogeneity, micronucleus formation and cytoplasmic double-stranded DNA (dsDNA) accumulation. Recent studies have revealed the “two sides” of CIN, i.e., moderate levels of CIN enable tumors to better adapt to changes in the tumor microenvironment, whereas excessive CIN leads to genetic catastrophe and cell death, triggers cellular paralysis and releases damage-associated molecular patterns (DAMPs), and enhances anti-tumor immune recognition. However, the relationship between CIN and the immune microenvironment currently remains a complex network, especially in colorectal cancer (CRC), where CIN-associated molecular mechanisms (e.g., the YY2/BUB1B axis) remodel the TME and overcome immunotherapeutic resistance in microsatellite-stabilized (MSS)-type CRC through the release of tumor neoantigens and pro-inflammatory factors (IL-1, IFNγ). In addition, combining serine/threonine kinase (AURK) inhibitors with immune checkpoint blockade, or targeting glycolytic and DNA repair pathways through metabolic reprogramming, provides new strategies to overcome CRC treatment resistance. In this review, we integrate basic mechanisms and clinical translational perspectives to propose a combination therapy strategy targeting the CIN-TME interaction network, which provides a theoretical basis and application prospect for optimizing colorectal cancer immunotherapy and expanding indications.
文章引用：边孜力, 潘运龙. 染色体不稳定性调控肿瘤免疫微环境：从基础机制到结直肠癌治疗突破[J]. 临床医学进展, 2025, 15(5): 1373-1379. https://doi.org/10.12677/acm.2025.1551504

参考文献

[1] Bach, D., Zhang, W. and Sood, A.K. (2019) Chromosomal Instability in Tumor Initiation and Development. Cancer Research, 79, 3995-4002. [Google Scholar] [CrossRef] [PubMed]
[2] Bolhaqueiro, A.C.F., Ponsioen, B., Bakker, B., Klaasen, S.J., Kucukkose, E., van Jaarsveld, R.H., et al. (2019) Ongoing Chromosomal Instability and Karyotype Evolution in Human Colorectal Cancer Organoids. Nature Genetics, 51, 824-834. [Google Scholar] [CrossRef] [PubMed]
[3] 刘芳芳, 张艳桥, 沈丹华, 等. 结直肠癌Lynch综合征MMR蛋白和微卫星不稳定性检测分析[J]. 中华病理学杂志, 2014, 43(9): 577-580.
[4] Hanahan, D. (2022) Hallmarks of Cancer: New Dimensions. Cancer Discovery, 12, 31-46. [Google Scholar] [CrossRef] [PubMed]
[5] Di Cosimo, S., Silvestri, M., De Marco, C., Calzoni, A., De Santis, M.C., Carnevale, M.G., et al. (2024) Low-Pass Whole Genome Sequencing of Circulating Tumor Cells to Evaluate Chromosomal Instability in Triple-Negative Breast Cancer. Scientific Reports, 14, Article No. 20479. [Google Scholar] [CrossRef] [PubMed]
[6] Rancati, G. and Pavelka, N. (2013) Karyotypic Changes as Drivers and Catalyzers of Cellular Evolvability: A Perspective from Non-Pathogenic Yeasts. Seminars in Cell & Developmental Biology, 24, 332-338. [Google Scholar] [CrossRef] [PubMed]
[7] Suijkerbuijk, S.J.E., van Osch, M.H.J., Bos, F.L., Hanks, S., Rahman, N. and Kops, G.J.P.L. (2010) Molecular Causes for BUBR1 Dysfunction in the Human Cancer Predisposition Syndrome Mosaic Variegated Aneuploidy. Cancer Research, 70, 4891-4900. [Google Scholar] [CrossRef] [PubMed]
[8] Hanks, S., Coleman, K., Reid, S., Plaja, A., Firth, H., FitzPatrick, D., et al. (2004) Constitutional Aneuploidy and Cancer Predisposition Caused by Biallelic Mutations in Bub1b. Nature Genetics, 36, 1159-1161. [Google Scholar] [CrossRef] [PubMed]
[9] Stingele, S., Stoehr, G., Peplowska, K., Cox, J., Mann, M. and Storchova, Z. (2012) Global Analysis of Genome, Transcriptome and Proteome Reveals the Response to Aneuploidy in Human Cells. Molecular Systems Biology, 8, Article No. 608. [Google Scholar] [CrossRef] [PubMed]
[10] Williams, B.R., Prabhu, V.R., Hunter, K.E., Glazier, C.M., Whittaker, C.A., Housman, D.E., et al. (2008) Aneuploidy Affects Proliferation and Spontaneous Immortalization in Mammalian Cells. Science, 322, 703-709. [Google Scholar] [CrossRef] [PubMed]
[11] Torres, E.M., Sokolsky, T., Tucker, C.M., Chan, L.Y., Boselli, M., Dunham, M.J., et al. (2007) Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast. Science, 317, 916-924. [Google Scholar] [CrossRef] [PubMed]
[12] Hervé, S., Scelfo, A., Bersano Marchisio, G., Grison, M., Vaidžiulytė, K., Dumont, M., et al. (2025) Chromosome Mis-Segregation Triggers Cell Cycle Arrest through a Mechanosensitive Nuclear Envelope Checkpoint. Nature Cell Biology, 27, 73-86. [Google Scholar] [CrossRef] [PubMed]
[13] López-García, C., Sansregret, L., Domingo, E., McGranahan, N., Hobor, S., Birkbak, N.J., et al. (2017) BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer. Cancer Cell, 31, 79-93. [Google Scholar] [CrossRef] [PubMed]
[14] Ohashi, A., Ohori, M., Iwai, K., Nakayama, Y., Nambu, T., Morishita, D., et al. (2015) Aneuploidy Generates Proteotoxic Stress and DNA Damage Concurrently with P53-Mediated Post-Mitotic Apoptosis in Sac-Impaired Cells. Nature Communications, 6, Article No. 7668. [Google Scholar] [CrossRef] [PubMed]
[15] Meena, J.K., Cerutti, A., Beichler, C., Morita, Y., Bruhn, C., Kumar, M., et al. (2015) Telomerase Abrogates Aneuploidy‐induced Telomere Replication Stress, Senescence and Cell Depletion. The EMBO Journal, 34, 1371-1384. [Google Scholar] [CrossRef] [PubMed]
[16] Andriani, G.A., Almeida, V.P., Faggioli, F., Mauro, M., Tsai, W.L., Santambrogio, L., et al. (2016) Whole Chromosome Instability Induces Senescence and Promotes SASP. Scientific Reports, 6, Article No. 35218. [Google Scholar] [CrossRef] [PubMed]
[17] Wu, Z., Qu, J. and Liu, G. (2024) Roles of Chromatin and Genome Instability in Cellular Senescence and Their Relevance to Ageing and Related Diseases. Nature Reviews Molecular Cell Biology, 25, 979-1000. [Google Scholar] [CrossRef] [PubMed]
[18] Santaguida, S., Richardson, A., Iyer, D.R., M'Saad, O., Zasadil, L., Knouse, K.A., et al. (2017) Chromosome Mis-Segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes That Are Eliminated by the Immune System. Developmental Cell, 41, 638-651.e5. [Google Scholar] [CrossRef] [PubMed]
[19] Krivega, M., Stiefel, C.M., Karbassi, S., Andersen, L.L., Chunduri, N.K., Donnelly, N., et al. (2021) Genotoxic Stress in Constitutive Trisomies Induces Autophagy and the Innate Immune Response via the cGAS-STING Pathway. Communications Biology, 4, Article No. 831. [Google Scholar] [CrossRef] [PubMed]
[20] Hosea, R., Hillary, S., Naqvi, S., Wu, S. and Kasim, V. (2024) The Two Sides of Chromosomal Instability: Drivers and Brakes in Cancer. Signal Transduction and Targeted Therapy, 9, Article No. 75. [Google Scholar] [CrossRef] [PubMed]
[21] Senovilla, L., Vitale, I., Martins, I., Tailler, M., Pailleret, C., Michaud, M., et al. (2012) An Immunosurveillance Mechanism Controls Cancer Cell Ploidy. Science, 337, 1678-1684. [Google Scholar] [CrossRef] [PubMed]
[22] Mackenzie, K.J., Carroll, P., Martin, C., Murina, O., Fluteau, A., Simpson, D.J., et al. (2017) cGAS Surveillance of Micronuclei Links Genome Instability to Innate Immunity. Nature, 548, 461-465. [Google Scholar] [CrossRef] [PubMed]
[23] Ahn, J., Xia, T., Rabasa Capote, A., Betancourt, D. and Barber, G.N. (2018) Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells. Cancer Cell, 33, 862-873.e5. [Google Scholar] [CrossRef] [PubMed]
[24] Sasaki, N., Homme, M., Murayama, T., Osaki, T., Tenma, T., An, T., et al. (2025) RNA Sensing Induced by Chromosome Missegregation Augments Anti-Tumor Immunity. Molecular Cell, 85, 770-786.e7. [Google Scholar] [CrossRef] [PubMed]
[25] Li, J., Hubisz, M.J., Earlie, E.M., Duran, M.A., Hong, C., Varela, A.A., et al. (2023) Non-Cell-Autonomous Cancer Progression from Chromosomal Instability. Nature, 620, 1080-1088. [Google Scholar] [CrossRef] [PubMed]
[26] Bakhoum, S.F. and Cantley, L.C. (2018) The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment. Cell, 174, 1347-1360. [Google Scholar] [CrossRef] [PubMed]
[27] Bakhoum, S.F., Silkworth, W.T., Nardi, I.K., Nicholson, J.M., Compton, D.A. and Cimini, D. (2014) The Mitotic Origin of Chromosomal Instability. Current Biology, 24, R148-R149. [Google Scholar] [CrossRef] [PubMed]
[28] He, B., Gnawali, N., Hinman, A.W., Mattingly, A.J., Osimani, A. and Cimini, D. (2019) Chromosomes Missegregated into Micronuclei Contribute to Chromosomal Instability by Missegregating at the Next Division. Oncotarget, 10, 2660-2674. [Google Scholar] [CrossRef] [PubMed]
[29] Krupina, K., Goginashvili, A. and Cleveland, D.W. (2021) Causes and Consequences of Micronuclei. Current Opinion in Cell Biology, 70, 91-99. [Google Scholar] [CrossRef] [PubMed]
[30] Fenech, M., Knasmueller, S., Bolognesi, C., Holland, N., Bonassi, S. and Kirsch-Volders, M. (2020) Micronuclei as Biomarkers of DNA Damage, Aneuploidy, Inducers of Chromosomal Hypermutation and as Sources of Pro-Inflammatory DNA in Humans. Mutation Research—Reviews in Mutation Research, 786, Article ID: 108342. [Google Scholar] [CrossRef] [PubMed]
[31] Zasadil, L.M., Britigan, E.M.C. and Weaver, B.A. (2013) 2n or Not 2n: Aneuploidy, Polyploidy and Chromosomal Instability in Primary and Tumor Cells. Seminars in Cell & Developmental Biology, 24, 370-379. [Google Scholar] [CrossRef] [PubMed]
[32] Nicholson, J.M., Macedo, J.C., Mattingly, A.J., Wangsa, D., Camps, J., Lima, V., et al. (2015) Chromosome Mis-Segregation and Cytokinesis Failure in Trisomic Human Cells. eLife, 4, e05068. [Google Scholar] [CrossRef] [PubMed]
[33] Passerini, V., Ozeri-Galai, E., de Pagter, M.S., Donnelly, N., Schmalbrock, S., Kloosterman, W.P., et al. (2016) The Presence of Extra Chromosomes Leads to Genomic Instability. Nature Communications, 7, Article No. 10754. [Google Scholar] [CrossRef] [PubMed]
[34] Fujiwara, T., Bandi, M., Nitta, M., Ivanova, E.V., Bronson, R.T. and Pellman, D. (2005) Cytokinesis Failure Generating Tetraploids Promotes Tumorigenesis in P53-Null Cells. Nature, 437, 1043-1047. [Google Scholar] [CrossRef] [PubMed]
[35] Harding, S.M., Benci, J.L., Irianto, J., Discher, D.E., Minn, A.J. and Greenberg, R.A. (2017) Mitotic Progression Following DNA Damage Enables Pattern Recognition within Micronuclei. Nature, 548, 466-470. [Google Scholar] [CrossRef] [PubMed]
[36] Bakhoum, S.F., Ngo, B., Laughney, A.M., Cavallo, J., Murphy, C.J., Ly, P., et al. (2018) Chromosomal Instability Drives Metastasis through a Cytosolic DNA Response. Nature, 553, 467-472. [Google Scholar] [CrossRef] [PubMed]
[37] McGranahan, N. and Swanton, C. (2017) Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell, 168, 613-628. [Google Scholar] [CrossRef] [PubMed]
[38] André, T., Shiu, K., Kim, T.W., Jensen, B.V., Jensen, L.H., Punt, C., et al. (2020) Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. New England Journal of Medicine, 383, 2207-2218. [Google Scholar] [CrossRef] [PubMed]
[39] Duan, W., Hosea, R., Wang, L., Ruan, C., Zhao, F., Liu, J., et al. (2025) Chromosome Missegregation Triggers Tumor Cell Pyroptosis and Enhances Anti‐Tumor Immunotherapy in Colorectal Cancer. Advanced Science, 12, e2409769. [Google Scholar] [CrossRef] [PubMed]
[40] Hosea, R., Duan, W., Meliala, I.T.S., Li, W., Wei, M., Hillary, S., et al. (2024) YY2/BUB3 Axis Promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability. Advanced Science, 11, e2308690. [Google Scholar] [CrossRef] [PubMed]
[41] Gupta, D., Kumar, M., Saifi, S., Rawat, S., Ethayathulla, A.S. and Kaur, P. (2024) A Comprehensive Review on Role of Aurora Kinase Inhibitors (AKIs) in Cancer Therapeutics. International Journal of Biological Macromolecules, 265, Article ID: 130913. [Google Scholar] [CrossRef] [PubMed]
[42] Kucharski, T.J., Vlasac, I.M., Lyalina, T., Higgs, M.R., Christensen, B.C., Bechstedt, S., et al. (2025) An Aurora Kinase A-BOD1L1-PP2A B56 Axis Promotes Chromosome Segregation Fidelity. Cell Reports, 44, Article ID: 115317. [Google Scholar] [CrossRef] [PubMed]
[43] Wang, X., Huang, J., Liu, F., Yu, Q., Wang, R., Wang, J., et al. (2023) Aurora a Kinase Inhibition Compromises Its Antitumor Efficacy by Elevating PD-L1 Expression. Journal of Clinical Investigation, 133, e161929. [Google Scholar] [CrossRef] [PubMed]
[44] Li, S., Ye, J., Yang, K., Xu, C., Qin, Z., Xue, Y., et al. (2025) Targeting the AURKB-MAD2L2 Axis Disrupts the DNA Damage Response and Glycolysis to Inhibit Colorectal Cancer Progression. Frontiers in Bioscience-Landmark, 30, Article No. 26532. [Google Scholar] [CrossRef] [PubMed]
[45] Shah, E.T., Molloy, C., Gough, M., Kryza, T., Samuel, S.G., Tucker, A., et al. (2024) Inhibition of Aurora B Kinase (AURKB) Enhances the Effectiveness of 5-Fluorouracil Chemotherapy against Colorectal Cancer Cells. British Journal of Cancer, 130, 1196-1205. [Google Scholar] [CrossRef] [PubMed]
[46] Ma, J., Huang, L., Hu, D., Zeng, S., Han, Y. and Shen, H. (2021) The Role of the Tumor Microbe Microenvironment in the Tumor Immune Microenvironment: Bystander, Activator, or Inhibitor? Journal of Experimental & Clinical Cancer Research, 40, Article No. 327. [Google Scholar] [CrossRef] [PubMed]
[47] Peng, Y.M., Luo, X.M. and Chen, J.Y. (2023) Research Progress and New Immunotherapy Strategies of Tumor Microenvironment Metabolism. Journal of Sichuan University. Medical Science Edition, 54, 505-509.

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