核苷酸代谢调控及其在肿瘤中的重编程与靶向治疗

doi:10.3969/j.issn.1674-490X.2026.05.001

摘要/Abstract

摘要： 核苷酸代谢通过从头合成与补救途径维持细胞内dNTP平衡与核苷酸池稳态,为DNA复制及RNA转录提供前体,同时参与能量代谢调控与表观修饰底物供给。肿瘤中该代谢网络发生重编程,受癌基因信号及肿瘤微环境的多重调控,驱动异常增殖并维持基因组稳定性。然而,核苷酸代谢关键酶的非经典功能与通路动态调控机制仍未充分阐明。临床应用中,现有靶向药物面临肿瘤特异性不足、毒副作用显著及易耐药等瓶颈。系统阐述肿瘤核苷酸代谢的调控机制及其在治疗耐药中的作用,以期为肿瘤精准靶向治疗提供新思路和理论依据。

关键词: 核苷酸代谢, 关键酶, 代谢重编程, 靶向治疗

Abstract: Nucleotide metabolism maintains intracellular dNTP balance and nucleotide pool homeostasis through de novo synthesis and salvage pathways, providing precursors for DNA replication and RNA transcription while also contributing to energy metabolism regulation and supplying substrates for epigenetic modifications. In tumors, this metabolic network undergoes reprogramming, driven by oncogenic signals and tumor microenvironment, which fuels abnormal proliferation and maintains genomic stability. However, the non-classical functions of key enzymes in nucleotide metabolism and the dynamic regulatory mechanisms of these pathways remain poorly understood. Clinically, available targeted therapies face significant bottlenecks, including insufficient tumor specificity, marked toxic side effects, and susceptibility to drug resistance. This review systematically elaborates on the regulatory mechanisms of tumor nucleotide metabolism, and its role in therapeutic resistance, aiming to provide new insights and a theoretical basis for precision targeted therapy of tumors.

Key words: nucleotide metabolism, key enzymes, metabolic reprogramming, targeted therapy

中图分类号:

R285

李晨阳,郄楚楚,李文娟. 核苷酸代谢调控及其在肿瘤中的重编程与靶向治疗[J]. 医学研究与教育, 2026, 43(5): 1-11.

Li Chenyang, Ke Chuchu, Li Wenjuan. Nucleotide metabolism regulation and its reprogramming in tumors with targeted therapeutic strategies[J]. Journal of Hebei Medical College for Continuing Education, 2026, 43(5): 1-11.

参考文献

[1] Siddiqui A, Ceppi P. A non-proliferative role of pyrimidine metabolism in cancer[J]. Mol Metab, 2020, 35: 100962. DOI: 10.1016/j.molmet.2020.02.005.
[2] Wang P C, Wang C, Wang Y S. Nucleotide salvage, genome instability, and potential therapeutic applications[J]. Nucleic Acids Res, 2026, 54(4): gkag099. DOI: 10.1093/nar/gkag099.
[3] Mullen N J, Singh P K. Nucleotide metabolism: a pan-cancer metabolic dependency[J]. Nat Rev Cancer, 2023, 23(5): 275-294. DOI: 10.1038/s41568-023-00557-7.
[4] Lane A N, Fan T W. Regulation of mammalian nucleotide metabolism and biosynthesis[J]. Nucleic Acids Res, 2015, 43(4): 2466-2485. DOI: 10.1093/nar/gkv047.
[5] Xiong G H, Yun F, Jiang L, et al. NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma[J]. Cell Death Differ, 2025, 32(12): 2193-2209. DOI: 10.1038/s41418-025-01525-4.
[6] Liu C L, Knudsen G M, Pedley A M, et al. Mapping post-translational modifications of de novo purine biosynthetic enzymes: implications for pathway regulation[J]. J Proteome Res, 2019, 18(5): 2078-2087. DOI: 10.1021/acs.jproteome.8b00969.
[7] Li M J, Jin C Z, Xu M L, et al. Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling[J]. Cell Commun Signal, 2017, 15(1): 52. DOI: 10.1186/s12964-017-0208-8.
[8] Geng P Y, Ye F, Dou P, et al. HIF-1α-HPRT1 axis promotes tumorigenesis and gefitinib resistance by enhancing purine metabolism in EGFR-mutant lung adenocarcinoma[J]. J Exp Clin Cancer Res, 2024, 43(1): 269. DOI: 10.1186/s13046-024-03184-8.
[9] Ni C M, Liu W Y, Zheng K L, et al. PI3K/c-Myc/AFF4 axis promotes pancreatic tumorigenesis through fueling nucleotide metabolism[J]. Int J Biol Sci, 2023, 19(6): 1968-1982. DOI: 10.7150/ijbs.77150.
[10] Luo B Y, Zhuang L, Huang J, et al. LncRNA ZFAS1 regulates ATIC transcription and promotes the proliferation and migration of hepatocellular carcinoma through the PI3K/AKT signaling pathway[J]. J Cancer Res Clin Oncol, 2024, 150(7): 351. DOI: 10.1007/s00432-024-05877-1.
[11] Zhang B, Chu W W, Li Z, et al. Circ-ATIC serves as a sponge of miR-326 to accelerate esophageal squamous cell carcinoma progression by targeting ID1[J]. Biochem Genet, 2022, 60(5): 1585-1600. DOI: 10.1007/s10528-021-10167-3.
[12] Villa E, Ali E S, Sahu U, et al. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides[J]. Cancers, 2019, 11(5): 688. DOI: 10.3390/cancers11050688.
[13] Cordova R A, Sommers N R, Law A S, et al. Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer[J]. Sci Signal, 2024, 17(864): eadp1375. DOI: 10.1126/scisignal.adp1375.
[14] Maiuolo J, Oppedisano F, Gratteri S, et al. Regulation of uric acid metabolism and excretion[J]. Int J Cardiol, 2016, 213: 8-14. DOI: 10.1016/j.ijcard.2015.08.109.
[15] Sun Q K, Zhang Z C, Lu Y J, et al. Loss of xanthine oxidoreductase potentiates propagation of hepatocellular carcinoma stem cells[J]. Hepatology, 2020, 71(6): 2033-2049. DOI: 10.1002/hep.30978.
[16] Chen J, Yang S Q, Li Y G, et al. De novo nucleotide biosynthetic pathway and cancer[J]. Genes Dis, 2023, 10(6): 2331-2338. DOI: 10.1016/j.gendis.2022.04.018.
[17] Liu Y X, Jiang H W, Liu J J, et al. DHODH as a targetable metabolic Achilles' heel for chemo-resistant B-ALL[J]. Blood, 2026: 2025029264. DOI: 10.1101/2025.01.27.635108.
[18] Tait-Mulder J, Hodge K, Sumpton D, et al. The conversion of formate into purines stimulates mTORC1 leading to CAD-dependent activation of pyrimidine synthesis[J]. Cancer Metab, 2020, 8(1): 20. DOI: 10.1186/s40170-020-00228-3.
[19] Liu F M, Gai X C, Wu Y T, et al. Oncogenic β-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer[J]. Proc Natl Acad Sci U S A, 2022, 119(39): e2202157119. DOI: 10.1073/pnas.2202157119.
[20] Walter M, Herr P. Re-discovery of pyrimidine salvage as target in cancer therapy[J]. Cells, 2022, 11(4): 739. DOI: 10.3390/cells11040739.
[21] Pham B Q, Yi S A, Ordureau A, et al. mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase[J]. Cell Rep, 2025, 44(1): 115179. DOI: 10.1016/j.celrep.2024.115179.
[22] Chakraborty S, Mukherjee P, Sengupta R. Ribonucleotide reductase: implications of thiol S-nitrosylation and tyrosine nitration for different subunits[J]. Nitric Oxide, 2022, 127: 26-43. DOI: 10.1016/j.niox.2022.07.002.
[23] Choi Y J, Lee K, Lee S Y, et al. p53 activation enhances the sensitivity of non-small cell lung cancer to the combination of SH003 and docetaxel by inhibiting de novo pyrimidine synthesis[J]. Cancer Cell Int, 2024, 24(1): 156. DOI:10.1186/s12935-024-03337-x.
[24] Li X L, Yang C, Zhang X H, et al. R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency[J]. Acta Biochim Biophys Sin, 2024, 56(12): 1875-1885. DOI: 10.3724/abbs.2024188.
[25] Helleday T, Rudd S G. Targeting the DNA damage response and repair in cancer through nucleotide metabolism[J]. Mol Oncol, 2022, 16(21): 3792-3810. DOI: 10.1002/1878-0261.13227.
[26] Zhou W H, Yao Y Y, Scott A J, et al. Purine metabolism regulates DNA repair and therapy resistance in glioblastoma[J]. Nat Commun, 2020, 11(1): 3811. DOI: 10.1038/s41467-020-17512-x.
[27] Li Q, Zhang L R, Yang Q, et al. Thymidine kinase 1 drives hepatocellular carcinoma in enzyme-dependent and-independent manners[J]. Cell Metab, 2023, 35(6): 912-927. DOI: 10.1016/j.cmet.2023.03.017.
[28] Martínez-Arribas B, Requena C E, Pérez-Moreno G, et al. DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools[J]. Cell Mol Life Sci, 2020, 77(8): 1645-1660. DOI: 10.1007/s00018-019-03250-x.
[29] Nunes C, Depestel L, Mus L, et al. RRM2 enhances MYCN^- driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition[J]. Sci Adv, 2022, 8(28): eabn1382. DOI: 10.1126/sciadv.abn1382.
[30] Gong C J, Liu H, Song R, et al. ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG[J]. Biochim Biophys Acta, 2016, 1859(4): 612-626. DOI: 10.1016/j.bbagrm.2016.02.012.
[31] Carnie C J, Götz M J, Palma-Chaundler C S, et al. Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS[J]. EMBO J, 2024, 43(12): 2397-2423. DOI: 10.1038/s44318-024-00108-2.
[32] Hung M H, Chang C W, Wang K C, et al. Purine anabolism creates therapeutic vulnerability in hepatocellular carcinoma through M6A-mediated epitranscriptomic regulation[J]. Hepatology, 2023, 78(5): 1462-1477. DOI: 10.1097/hep.0000000000000420.
[33] Zhang Y Y, Zhang H Y, Li M C, et al. Lnc-TPT1-AS1/CBP/ATIC axis mediated purine metabolism activation promotes breast cancer progression[J]. Cancer Sci, 2025, 116(6): 1565-1578. DOI: 10.1111/cas.70045.
[34] Huo F C, Xie M, Zhu Z M, et al. SHMT2 promotes the tumorigenesis of renal cell carcinoma by regulating the M6A modification of PPAT[J]. Genomics, 2022, 114(4): 110424. DOI: 10.1016/j.ygeno.2022.110424.
[35] Li S Y, Liu Y, Wu X, et al. The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism[J]. Cell Rep, 2025, 44(5): 115661. DOI: 10.1016/j.celrep.2025.115661.
[36] Xing H W, Ma F Q, Li P H, et al. METTL1-mediated M7G modification of ASNS mRNA regulates asparagine metabolism reprogramming to promote hepatocellular carcinoma progression[J]. Oncogene, 2026, 45(23): 2269-2285. DOI: 10.1038/s41388-026-03806-9.
[37] Wu Y M, Chen Z J, Xie G Y, et al. RNA m¹A methylation regulates glycolysis of cancer cells through modulating ATP5D[J]. Proc Natl Acad Sci U S A, 2022, 119(28): e2119038119. DOI: 10.1073/pnas.2119038119.
[38] Wu H L, Gong Y, Ji P, et al. Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy[J]. J Hematol Oncol, 2022, 15(1): 45. DOI: 10.1186/s13045-022-01263-x.
[39] Madsen H B, Peeters M J, Straten P T, et al. Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function[J]. Curr Opin Biotechnol, 2023, 84: 103008. DOI: 10.1016/j.copbio.2023.103008.
[40] Wang S, Gao S S, Zhou D X, et al. The role of the CD39-CD73-adenosine pathway in liver disease[J]. J Cell Physiol, 2021, 236(2): 851-862. DOI: 10.1002/jcp.29932.
[41] Boison D, Yegutkin G G. Adenosine metabolism: emerging concepts for cancer therapy[J]. Cancer Cell, 2019, 36(6): 582-596. DOI: 10.1016/j.ccell.2019.10.007.
[42] Abt E R, Rashid K, Le T M, et al. Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity[J]. J Clin Investig, 2022, 132(16): e160852. DOI: 10.1172/jci160852.
[43] Duan Y R, Hu Z Q, Han P, et al. ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion[J]. Nat Cell Biol, 2025, 27(4): 668-682. DOI: 10.1038/s41556-025-01627-8.
[44] Ariav Y, Ch'ng J H, Christofk H R, et al. Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response[J]. Sci Adv, 2021, 7(21): eabg6165. DOI: 10.1126/sciadv.abg6165.
[45] Moloney M, Faulkner D, Link E, et al. Feasibility of 5-fluorouracil pharmacokinetic monitoring using the My-5FU PCM^TM system in a quaternary oncology centre[J]. Cancer Chemother Pharmacol, 2018, 82(5): 865-876. DOI: 10.1007/s00280-018-3679-4.
[46] Parker W B. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer[J]. Chem Rev, 2009, 109(7): 2880-2893. DOI: 10.1021/cr900028p.
[47] Ding M, Ma C S, Lin Y Y, et al. Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma[J]. Cell Death Dis, 2025, 16(1): 179. DOI: 10.1038/s41419-025-07502-6.
[48] Zheng M M, Li J Y, Guo H J, et al. IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy[J]. Acta Pharmacol Sin, 2025, 46(4): 1058-1067. DOI: 10.1038/s41401-024-01411-8.
[49] Ma J S, Zhao J B, Zhang C S, et al. Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy[J]. Nat Commun, 2025, 16(1): 5006. DOI: 10.1038/s41467-025-60144-2.
[50] Wang Y J, Chai Y Y, Liu Y F, et al. Inhibition of tumor cell macropinocytosis driver DHODH reverses immunosuppression and overcomes anti-PD1 resistance[J]. Immunity, 2025, 58(10): 2456-2471. DOI: 10.1016/j.immuni.2025.07.013.
[51] Christian S, Merz C, Evans L, et al. The novel dihydroorotate dehydrogenase(DHODH)inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies[J]. Leukemia, 2019, 33(10): 2403-2415. DOI: 10.1038/s41375-019-0461-5.
[52] Sykes D B. The emergence of dihydroorotate dehydrogenase(DHODH)as a therapeutic target in acute myeloid leukemia[J]. Expert Opin Ther Targets, 2018, 22(11): 893-898. DOI: 10.1080/14728222.2018.1536748.
[53] Madak J T, Bankhead A, Cuthbertson C R, et al. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer[J]. Pharmacol Ther, 2019, 195: 111-131. DOI: 10.1016/j.pharmthera.2018.10.012.
[54] Yan S C, Hu X M, Wu Y, et al. ITGA4 contributes to 5-fluorouracil resistance by up-regulating PI3K/AKT signaling: evidence from network pharmacology, molecular docking and experimental verification[J]. Drug Des Dev Ther, 2025, 19: 4105-4122. DOI: 10.2147/DDDT.S474421.
[55] Balboni B, El Hassouni B, Honeywell R J, et al. RX-3117(fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment[J]. Expert Opin Investig Drugs, 2019, 28(4): 311-322. DOI: 10.1080/13543784.2019.1583742.
[56] Wu Z, Bezwada D, Cai F, et al. Electron transport chain inhibition increases cellular dependence on purine transport and salvage[J]. Cell Metab, 2024, 36(7): 1504-1520. DOI: 10.1016/j.cmet.2024.05.014.
[57] 刘佳, 石岳泉, 刘潇衍,等. 腺苷/A2AR信号通路阻断在肿瘤治疗中的应用 [J]. 中国肺癌杂志, 2022, 25(7): 460-467.DOI: 10.3779/j.issn.1009-3419.2022.102.24.
[58] Chen Q D, Yin H L, He J Y, et al. Tumor microenvironment responsive CD8⁺ T cells and myeloid-derived suppressor cells to trigger CD73 inhibitor AB680-based synergistic therapy for pancreatic cancer[J]. Adv Sci, 2023, 10(33): 2302498. DOI: 10.1002/advs.202302498.
[59] Zhou Q X, Lin M H, Feng X, et al. Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism[J]. J Exp Med, 2020, 217(8): e20191779. DOI: 10.1084/jem.20191779.
[60] Nwosu Z C, Ward M H, Sajjakulnukit P, et al. Uridine-derived ribose fuels glucose-restricted pancreatic cancer[J]. Nature, 2023, 618(7963): 151-158. DOI: 10.1038/s41586-023-06073-w.
[61] Zou S M, Qin B F, Yang Z Q, et al. CSN6 mediates nucleotide metabolism to promote tumor development and chemoresistance in colorectal cancer[J]. Cancer Res, 2023, 83(3): 414-427. DOI: 10.1158/0008-5472.CAN-22-2145.
[62] Perrault E N, Shireman J M, Ali E S, et al. Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production[J]. Sci Adv, 2023, 9(20): eade7236. DOI: 10.1126/sciadv.ade7236.
[63] Kim N, Yang C. Sodium butyrate enhances 5-fluorouracil sensitivity through thymidylate synthase regulation and cell-cycle modulation in gastric cancer[J]. Mol Nutr Food Res, 2025, 69(19): e70152. DOI: 10.1002/mnfr.70152.
[64] Huang X L, Liang J Q, Yi Y J, et al. Targeting inosine metabolism to enhance EGFR-targeted therapy in lung adenocarcinoma[J]. Cancer Lett, 2025, 634: 218069. DOI: 10.1016/j.canlet.2025.218069.
[65] Huang F, Huffman K E, Wang Z X, et al. Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer[J]. J Clin Invest, 2021, 131(1): e139929. DOI: 10.1172/JCI139929.
[66] Scolaro T, Manco M, Pecqueux M, et al. Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance[J]. Nat Cancer, 2024, 5(8): 1206-1226. DOI: 10.1038/s43018-024-00771-8.