The role of ubiquitin-like modification in tumor immunity

doi:10.3969/j.issn.1006-7795.2026.02.009

Abstract

Abstract: Ubiquitin-like modification (ULM) is defined as a reversible post-translational modification that modulates protein function through the conjugation of ubiquitin-like proteins (UBLs). Numerous studies have documented the regulatory role of ULM in cancer immunity by helping immune cell, cytokine, and tumor microenvironment cellular functionality. This paper analyzes the constituent and modification mechanisms of some common ULM systems, and examines UBLs like neural precursor cell expressed developmentally down-regulated 8 (NEDD8), small ubiquitin-related modifier (SUMO), human leukocyte antigen-F adjacent transcript 10 (FAT10) and ubiquitin-fold modifier 1 (UFM1) and their tumor immune regulatory role in tumor immunity alongside their prospective therapeutic role in cancer.

Key words: ubiquitin-like modification (ULM) , ubiquitin-like proteins (UBLs), neural precursor cell expressed developmentally down-regulated 8（NEDD8）, small ubiquitin-related modifier（SUMO）, human leukocyte antigen-F adjacent transcript 10（FAT10）, ubiquitin-fold modifier 1（UFM1）, tumor immunity；tumor treatment

CLC Number:

R730.3

Peng Zhaoqi, Xie Ping. The role of ubiquitin-like modification in tumor immunity[J]. Journal of Capital Medical University, 2026, 47(2): 285-289.

References

［1］Gâtel P, Piechaczyk M, Bossis G. Ubiquitin, SUMO, and Nedd8 as therapeutic targets in cancer［J］. Adv Exp Med Biol, 2020, 1233: 29－54.
［2］Lee B, Jeong H, Kim Y, et al. Ubiquitin-like proteins in autoimmune diseases: current evidence and therapeutic opportunities［J］. Immune Netw, 2025, 25(3): e21.
［3］Frickel E M, Quesada V, Muething L, et al. Apicomplexan UCHL3 retains dual specificity for ubiquitin and Nedd8 throughout evolution［J］. Cell Microbiol, 2007, 9(6): 1601－1610.
［4］Watson I R, Irwin M S, Ohh M. NEDD8 pathways in cancer, sine Quibus non［J］. Cancer Cell, 2011, 19(2): 168－176.
［5］Zhang S Z, Yu Q, Li Z J, et al. Protein neddylation and its role in health and diseases［J］. Signal Transduct Target Ther, 2024, 9(1): 85.
［6］Tatham M H, Jaffray E, Vaughan O A, et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9［J］. J Biol Chem, 2001, 276(38): 35368－35374.
［7］Hammoudi V, Vlachakis G, Schranz M E, et al. Whole-genome duplications followed by tandem duplications drive diversification of the protein modifier SUMO in angiosperms［J］. New Phytol, 2016, 211(1): 172－185.
［8］Chang H M, Yeh E T H. SUMO: from bench to bedside［J］. Physiol Rev, 2020, 100(4): 1599－1619.
［9］Bettermann K, Benesch M, Weis S, et al. SUMOylation in carcinogenesis［J］. Cancer Lett, 2012, 316(2): 113－125.
［10］Komatsu M, Inada T, Noda N N. The UFM1 system: working principles, cellular functions, and pathophysiology［J］. Mol Cell, 2024, 84(1): 156－169.
［11］白睿, 孙文洁. UFMylation: 癌症治疗中一种有前景的翻译后修饰［J］. 武汉大学学报: 医学版, 2025, 46(5): 677－682.
［12］沈关心, 赵富玺. 医学免疫学［M］. 北京: 人民卫生出版社, 2019: 398.
［13］李维娜, 雷小英,李萌,等. 肿瘤免疫治疗的机制、策略与临床进展［J］. 空军军医大学学报, 2025, 46 (11): 1401-1408.
［14］孙辉, 钮玉平. 肿瘤免疫治疗的研究进展［J］. 兰州大学学报(医学版), 2023, 49 (12): 1-6.
［15］Jantrapirom S, Piccolo L L, Pruksakorn D, et al.Ubiquilin networking in cancers［J］.Cancers(Basel),2020,12(6):1586.
［16］Petillo S, Sproviero E, Loconte L, et al. NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells［J］. Cell Death Dis, 2023, 14(7): 438.
［17］Jiang Y, Gao S J, Sun H, et al. Targeting NEDD8 suppresses surgical stress-facilitated metastasis of colon cancer via restraining regulatory T cells［J］. Cell Death Dis, 2024, 15(1): 8.
［18］Papakyriacou I, Kutkaite G, Rúbies Bedós M, et al. Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer［J］. Nat Commun, 2024, 15(1): 3581.
［19］Nakagawa K, Yokosawa H. PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1［J］. FEBS Lett, 2002, 530(1/3): 204-208.
［20］Han K J, Jiang L, Shu H B. Regulation of IRF2 transcriptional activity by its sumoylation［J］. Biochem Biophys Res Commun, 2008, 372(4): 772-778.
［21］Ding X, Wang A B, Ma X P, et al. Protein SUMOylation is required for regulatory T cell expansion and function［J］. Cell Rep, 2016, 16(4): 1055-1066.
［22］He Z H, Zhang J, Huang Z F, et al. Sumoylation of RORγt regulates TH17 differentiation and thymocyte development［J］. Nat Commun, 2018, 9(1): 4870.
［23］Tharuka M D N, Courelli A S, Chen Y. Immune regulation by the SUMO family［J］. Nat Rev Immunol, 2025, 25(8): 608-620.
［24］Demel U M, Böger M, Yousefian S, et al. Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer［J］. J Clin Invest, 2022, 132(9): e152383.
［25］Wang Z B, Pan B L, Qiu J C, et al. SUMOylated IL-33 in the nucleus stabilizes the transcription factor IRF1 in hepatocellular carcinoma cells to promote immune escape［J］. Sci Signal, 2023, 16(776): eabq3362.
［26］Xiang S F, Shao X J, Cao J, et al. FAT10: function and relationship with cancer［J］. Curr Mol Pharmacol, 2020, 13(3): 182-191.
［27］Jiang X J, Wang J, Deng X Y, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape［J］. Mol Cancer, 2019, 18(1): 10.
［28］孔德沈玥, 王昆华,张尊月,等. 外泌体程序性死亡配体-1介导肿瘤免疫逃避机制研究进展［J］.中华肿瘤防治杂志, 2020, 27 (10): 827-834.
［29］张文明. 类泛素蛋白FAT10通过促进CSTF2诱导PD-L13'UTR缩短介导肿瘤免疫逃逸的机制研究［D］. 南昌: 南昌大学, 2023.
［30］Aichem A, Groettrup M. The ubiquitin-like modifier FAT10 in cancer development［J］. Int J Biochem Cell Biol, 2016, 79: 451-461.
［31］Zou Y K, Wang Z X, Jiang Q, et al. UFMylation: a supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors［J］. Proc Natl Acad Sci U S A, 2025, 122(27): e2500562122.
［32］He C, Xing X X, Chen H Y, et al. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity［J］. Mol Cell, 2024, 84(6): 1120-1138.e8.
［33］Balce R D, Wang Y T, McAllaster M R, et al. UFMylation inhibits the proinflammatory capacity of interferon-γ-activated macrophages［J］. Proc Natl Acad Sci U S A, 2021, 118(1): e2011763118.
［34］郭亚辉, 陆鹏, 王玉斌, 等. 抗肿瘤NEDD8活化酶抑制剂的研究进展［J］. 中国药科大学学报, 2017, 48(6): 646-653.
［35］魏军, 周联明, 蒋叶平. NEDD8在胆囊癌发生发展中的作用机制研究［J］. 南昌大学学报: 医学版, 2025, 65(1): 21-25, 30.
［36］王微, 孙峥嵘. 小泛素样修饰(SUMO)与肿瘤发生发展的机制研究进展［J］. 现代肿瘤医学, 2024, 32(11): 2084-2088.［37］姜忠敏, 刘晓智, 赵坡. 小泛素相关修饰物异常表达在常见恶性肿瘤发生发展中的作用机制研究进展［J］. 山东医药, 2021, 61(12): 107-111.
［38］张梅, 王淼, 伍会健. SUMO化修饰系统及其在肿瘤发展中的作用［J］. 中国细胞生物学学报, 2015, 37(10): 1458-1464.
［39］Giri R, Yeh H H, Wu C H, et al. SUMO-1 overexpression increases RbAp46 protein stability and suppresses cell growth［J］. Anticancer Res, 2008, 28(6A): 3749-3756.
［40］张乐, 胡静仪, 杨萍, 等. 蛋白质小泛素相关修饰物与肿瘤的研究进展［J］. 江苏医药, 2022, 48(6): 624-628.
［41］Qiu Y M, Che B, Zhang W M, et al. The ubiquitin-like protein FAT10 in hepatocellular carcinoma cells limits the efficacy of anti-VEGF therapy by accelerating VEGF-independent angiogenesis［J］. J Adv Res, 2023, 59: 97-109.
［42］朱锦锋. FAT10通过EMT降低胰腺癌细胞对吉西他滨化疗敏感性的机制研究［D］. 南昌: 南昌大学, 2022.
［43］Liu B T, Yang T T, Zhang J L, et al. UFMylation in tumorigenesis: mechanistic insights and therapeutic opportunities［J］. Cell Signal, 2025, 129: 111657.

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