Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
Google Scholar
Provencio M, Nadal E, Gonzalez-Larriba JL, Martinez-Marti A, Bernabe R, Bosch-Barrera J, et al. Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2023;389:504–13.
Google Scholar
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.
Google Scholar
Kim TY, Jackson S, Xiong Y, Whitsett TG, Lobello JR, Weiss GJ, et al. CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth. Proc Natl Acad Sci USA. 2013;110:16868–73.
Google Scholar
Sapozhnikov DM, Szyf M. Unraveling the functional role of DNA demethylation at specific promoters by targeted steric blockage of DNA methyltransferase with CRISPR/dCas9. Nat Commun. 2021;12:5711.
Google Scholar
Sekeres MA, Taylor J. Diagnosis and treatment of myelodysplastic syndromes: a review. JAMA. 2022;328:872–80.
Google Scholar
Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–40.
Google Scholar
Momparler RL. Epigenetic therapy of non-small cell lung cancer using decitabine (5-aza-2’-deoxycytidine). Front Oncol. 2013;3:188.
Google Scholar
Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, et al. Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin Cancer Res. 2006;12:5777–85.
Google Scholar
Momparler RL. Epigenetic therapy of cancer with 5-aza-2’-deoxycytidine (decitabine). Semin Oncol. 2005;32:443–51.
Google Scholar
Liu J, He Q-L, Zhou J, Chikarmane R, Hauk G, Rachakonda A, et al. Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance. bioRxiv [Preprint]. 2024. Available from: https://doi.org/10.1101/2024.05.19.594134.
Oellerich T, Schneider C, Thomas D, Knecht KM, Buzovetsky O, Kaderali L, et al. Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML. Nat Commun. 2019;10:3475.
Google Scholar
Mahfouz RZ, Jankowska A, Ebrahem Q, Gu X, Visconte V, Tabarroki A, et al. Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res. 2013;19:938–48.
Google Scholar
Carnie CJ, Gotz MJ, Palma-Chaundler CS, Weickert P, Wanders A, Serrano-Benitez A, et al. Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS. EMBO J. 2024;43:2397–423.
Google Scholar
Rothenburger T, Thomas D, Schreiber Y, Wratil PR, Pflantz T, Knecht K, et al. Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells. J Exp Clin Cancer Res. 2021;40:317.
Google Scholar
Aye Y, Li M, Long MJ, Weiss RS. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies. Oncogene. 2015;34:2011–21.
Google Scholar
Foskolou IP, Jorgensen C, Leszczynska KB, Olcina MM, Tarhonskaya H, Haisma B, et al. Ribonucleotide reductase requires subunit switching in hypoxia to maintain DNA replication. Mol Cell. 2017;66:206–20.e9.
Google Scholar
Huang Q, Li F, Hu H, Fang Z, Gao Z, Xia G, et al. Loss of TSC1/TSC2 sensitizes immune checkpoint blockade in non-small cell lung cancer. Sci Adv. 2022;8:eabi9533.
Google Scholar
Anders NM, Liu J, Wanjiku T, Giovinazzo H, Zhou J, Vaghasia A, et al. Simultaneous quantitative determination of 5-aza-2’-deoxycytidine genomic incorporation and DNA demethylation by liquid chromatography tandem mass spectrometry as exposure-response measures of nucleoside analog DNA methyltransferase inhibitors. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1022:38–45.
Google Scholar
Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer. 2013;108:2505–15.
Google Scholar
Fajardo-Orduna GR, Ledesma-Martinez E, Aguiniga-Sanchez I, Mora-Garcia ML, Weiss-Steider B, Santiago-Osorio E. Inhibitors of chemoresistance pathways in combination with Ara-C to overcome multidrug resistance in AML. A mini review. Int J Mol Sci. 2021;22:4955.
Vijayaraghavalu S, Labhasetwar V. Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion. Cancer Lett. 2013;331:122–9.
Google Scholar
Nakamura M, Nishikawa J, Saito M, Sakai K, Sasaki S, Hashimoto S, et al. Decitabine inhibits tumor cell proliferation and up-regulates e-cadherin expression in Epstein-Barr virus-associated gastric cancer. J Med Virol. 2017;89:508–17.
Google Scholar
Chiou LW, Chan CH, Jhuang YL, Yang CY, Jeng YM. DNA replication stress and mitotic catastrophe mediate sotorasib addiction in KRAS(G12C)-mutant cancer. J Biomed Sci. 2023;30:50.
Google Scholar
Okonska A, Buhler S, Rao V, Ronner M, Blijlevens M, van der Meulen-Muileman IH, et al. Functional genomic screen in mesothelioma reveals that loss of function of BRCA1-associated protein 1 induces chemoresistance to ribonucleotide reductase inhibition. Mol Cancer Ther. 2020;19:552–63.
Google Scholar
Zavras PD, Shastri A, Goldfinger M, Verma AK, Saunthararajah Y. Clinical trials assessing hypomethylating agents combined with other therapies: causes for failure and potential solutions. Clin Cancer Res. 2021;27:6653–61.
Google Scholar
Tsujioka T, Yokoi A, Itano Y, Takahashi K, Ouchida M, Okamoto S, et al. Five-aza-2’-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells. Sci Rep. 2015;5:16709.
Google Scholar
Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci USA. 2005;102:15785–90.
Google Scholar
Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008;358:1118–28.
Google Scholar
Orta ML, Hoglund A, Calderon-Montano JM, Dominguez I, Burgos-Moron E, Visnes T, et al. The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2’-deoxycytidine lesions. Nucleic Acids Res. 2014;42:9108–20.
Google Scholar
Besse B, Olaussen KA, Soria JC. ERCC1 and RRM1: ready for prime time? J Clin Oncol. 2013;31:1050–60.
Google Scholar
Alexandraki A, Strati K. Decitabine treatment induces a viral mimicry response in cervical cancer cells and further sensitizes cells to chemotherapy. Int J Mol Sci. 2022;23:14042.
Chung MH, Aimaier R, Yu Q, Li H, Li Y, Wei C, et al. RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST. Cell Oncol (Dordr). 2023;46:1399–413.
Google Scholar
Blagitko-Dorfs N, Jiang Y, Duque-Afonso J, Hiller J, Yalcin A, Greve G, et al. Epigenetic priming of AML blasts for all-trans retinoic acid-induced differentiation by the HDAC class-I selective inhibitor entinostat. PLoS ONE. 2013;8:e75258.
Google Scholar
Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162:974–86.
Google Scholar
Leonard M, Westra S, Phatak A, Lambert M, van den Hurk B, McInnes K, et al. A compound event framework for understanding extreme impacts. WIREs Clim Change. 2014;5:113–28.
Google Scholar
SCANDURA M, IACOLINA L, APOLLONIO M. Genetic diversity in the European wild boar Pig sow: phylogeography, population structure and wild x domestic hybridization. Mammal Rev. 2011;41:125–37.
Google Scholar
Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, et al. Autistic-like behavior and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488:647–51.
Google Scholar
Ye L, Allen WE, Thompson KR, Tian Q, Hsueh B, Ramakrishnan C, et al. Wiring and molecular features of prefrontal ensembles representing distinct experiences. Cell. 2016;165:1776–88.
Google Scholar
Afratis NA, Parikh S, Adir I, Parikh R, Solomonov I, Kollet O, et al. Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models. Sci Transl Med. 2025;17:eadp3236.
Google Scholar
Abu-Sultanah M, Zhou Z, Jiang C, Mitchell DK, Bessler WK, Jiang L, et al. TGFbeta-dependent signaling drives tumor growth and aberrant extracellular matrix dynamics in NF1-associated plexiform neurofibroma. Sci Adv. 2025;11:eadu0772.
Google Scholar
Nephew KP. Turning up the heat on the pancreatic tumor microenvironment by epigenetic priming. Cancer Res. 2020;80:4610–1.
Google Scholar
Han P, Hou Y, Zhao Y, Liu Y, Yu T, Sun Y, et al. Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia. Blood. 2021;138:674–88.
Google Scholar
Dubois F, Keller M, Calvayrac O, Soncin F, Hoa L, Hergovich A, et al. RASSF1A suppresses the invasion and metastatic potential of human non-small cell lung cancer cells by inhibiting YAP activation through the GEF-H1/RhoB pathway. Cancer Res. 2016;76:1627–40.
Google Scholar
Kitajima S, Tani T, Springer BF, Campisi M, Osaki T, Haratani K, et al. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer. Cancer Cell. 2022;40:1128–44.e8.
Google Scholar
Li X, Li Y, Dong L, Chang Y, Zhang X, Wang C, et al. Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models. J Clin Invest. 2023;133:e165673.
Dunphy G, Flannery SM, Almine JF, Connolly DJ, Paulus C, Jonsson KL, et al. Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-kappaB signaling after Nnuclear DNA damage. Mol Cell. 2018;71:745–60e5.
Google Scholar
Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–803.
Google Scholar
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.
Google Scholar
Christman JK. 5-Azacytidine and 5-aza-2’-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21:5483–95.
Google Scholar
Oz S, Raddatz G, Rius M, Blagitko-Dorfs N, Lubbert M, Maercker C, et al. Quantitative determination of decitabine incorporation into DNA and its effect on mutation rates in human cancer cells. Nucleic Acids Res. 2014;42:e152.
Google Scholar
Linnekamp JF, Butter R, Spijker R, Medema JP, van Laarhoven HWM. Clinical and biological effects of demethylating agents on solid tumours—a systematic review. Cancer Treat Rev. 2017;54:10–23.
Google Scholar
Liao WY, Shih JY, Chang GC, Cheng YK, Yang JC, Chen YM, et al. Genetic polymorphism of XRCC1 Arg399Gln is associated with survival in non-small-cell lung cancer patients treated with gemcitabine/platinum. J Thorac Oncol. 2012;7:973–81.
Google Scholar
Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G, et al. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013;31:2404–12.
Google Scholar
Mao G, Shan C, Li W, Liang B, Ma L, Zhang S. High expression of RRM1 mediated by ncRNAs correlates with poor prognosis and tumor immune infiltration of hepatocellular carcinoma. Int J Gen Med. 2022;15:2607–20.
Google Scholar
Tsyganov MM, Ibragimova MK, Garbukov EY, Tsydenova IA, Gaptulbarova KA, Dolgasheva DS, et al. Predictive and prognostic significance of mRNA expression and DNA copies aberrations of ERCC1, RRM1, TOP1, TOP2A, TUBB3, TYMS, and GSTP1 genes in patients with breast cancer. Diagnostics (Basel). 2022;12:405.
Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008;112:2341–51.
Google Scholar
Ghanim V, Herrmann H, Heller G, Peter B, Hadzijusufovic E, Blatt K, et al. 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand. Blood. 2012;119:4242–52.
Google Scholar
Orta ML, Calderon-Montano JM, Dominguez I, Pastor N, Burgos-Moron E, Lopez-Lazaro M, et al. 5-Aza-2’-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair. Nucleic Acids Res. 2013;41:5827–36.
Google Scholar
Yang S, Wang R, Liu L, Xu F, Zhao X, Yao Z, et al. RRM1 promotes homologous recombination and radio/chemo-sensitivity via enhancing USP11 and E2F1-mediated RAD51AP1 transcription. Cell Death Discov. 2024;10:496.
Google Scholar
Huang X, Yu S, Wei W, Tao W, Cai T, Wen L, et al. Fe–S protein FDX1 triggers tumor-intrinsic innate immunity via mitochondrial nucleic acids release to orchestrate ferroptosis in CCRCC. Adv Sci (Weinh). 2025;13:e18323.
Gleneadie HJ, Baker AH, Batis N, Bryant J, Jiang Y, Clokie SJH, et al. The anti-tumour activity of DNA methylation inhibitor 5-aza-2’-deoxycytidine is enhanced by the common analgesic paracetamol through induction of oxidative stress. Cancer Lett. 2021;501:172–86.
Google Scholar
Goyal A, Bauer J, Hey J, Papageorgiou DN, Stepanova E, Daskalakis M, et al. DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts. Nat Commun. 2023;14:6731.
Google Scholar
Yu H, Liu W, Ding K, Wu J, Wang C, Wang S, et al. Sequential release HydroLipo system for STING gene epigenetic reprogramming and immune activation in glioblastoma. Adv Sci (Weinh). 2024;12:e2408323.
Hu J, Sanchez-Rivera FJ, Wang Z, Johnson GN, Ho YJ, Ganesh K, et al. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature. 2023;616:806–13.
Google Scholar
Falahat R, Berglund A, Putney RM, Perez-Villarroel P, Aoyama S, Pilon-Thomas S, et al. Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. Proc Natl Acad Sci USA. 2021;118:e2013598118.
Mehdipour P, Marhon SA, Ettayebi I, Chakravarthy A, Hosseini A, Wang Y, et al. Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency. Nature. Rev. 2020;588:169–7
Google Scholar
Kim H, Kim H, Feng Y, Li Y, Tamiya H, Tocci S, et al. PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Sci Transl Med. 2020;12:eaaz5683.
Sasaki N, Homme M, Murayama T, Osaki T, Tenma T, An T, et al. RNA sensing induced by chromosome missegregation augments anti-tumor immunity. Mol Cell. 2025;85:770–86e7.
