Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells

Abstract

Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.

Keywords

DNA methylation / epigenetics strategy / histone modification / immune suppressive cell / non-coding RNA

References

[1] Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41(3):421–433.

[2] Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17(8):807–821.

[3] Tümen D, Heumann P, Gülow K, Demirci CN, Cosma LS, Müller M, et al. Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma. Biomedicines. 2022;10(12):3202.

[4] Garcia-Lezana T, Lopez-Canovas JL, Villanueva A. Signaling pathways in hepatocellular carcinoma. Adv Cancer Res. 2021;149:63–101.

[5] Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell. 2022;13(12):877–919.

[6] Aso K, Kono M, Kanda M, Kudo Y, Sakiyama K, Hisada R, et al. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming. Nat Commun. 2023;14(1):984.

[7] Liu M, Li S, Li MO. TGF-β Control of Adaptive Immune Tolerance: A Break From Treg Cells. Bioessays. 2018;40(11):e1800063.

[8] Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, et al. Adaptive plasticity of IL-10(+) and IL-35(+) T(reg) cells cooperatively promotes tumor T cell exhaustion. Nat Immunol. 2019;20(6):724–735.

[9] Caronni N, La Terza F, Vittoria FM, Barbiera G, Mezzanzanica L, Cuzzola V, et al. IL-1β(+) macrophages fuel pathogenic inflammation in pancreatic cancer. Nature. 2023;623(7986):415–422.

[10] Fabian KP, Padget MR, Donahue RN, Solocinski K, Robbins Y, Allen CT, et al. PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations. J Immunother Cancer. 2020;8(1):e000450.

[11] Watanabe T, Ishino T, Ueda Y, Nagasaki J, Sadahira T, Dansako H, et al. Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity. Cancer Sci. 2023;114(5):1859–1870.

[12] Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276(1):97–111.

[13] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–174.

[14] Mortezaee K. Myeloid-derived suppressor cells in cancer immunotherapy-clinical perspectives. Life Sci. 2021;277:119627.

[15] Xu C, Xiao M, Li X, Xin L, Song J, Zhan Q, et al. Origin, activation, and targeted therapy of glioma-associated macrophages. Front Immunol. 2022;13:974996.

[16] Mishra AK, Banday S, Bharadwaj R, Ali A, Rashid R, Kulshreshtha A, et al. Macrophages as a Potential Immunotherapeutic Target in Solid Cancers. Vaccines (Basel). 2022;11(1):55.

[17] Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.

[18] Chavez-Galan L, Olleros ML, Vesin D, Garcia I. Much More than M1 and M2 Macrophages, There are also CD169(+) and TCR(+) Macrophages. Front Immunol. 2015;6:263.

[19] Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26(1):78.

[20] Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010;70(14):5728–5739.

[21] Cavalleri T, Greco L, Rubbino F, Hamada T, Quaranta M, Grizzi F, et al. Tumor-associated macrophages and risk of recurrence in stage III colorectal cancer. J Pathol Clin Res. 2022;8(4):307–312.

[22] Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344(6186):921–925.

[23] Palaga T, Wongchana W, Kueanjinda P. Notch Signaling in Macrophages in the Context of Cancer Immunity. Front Immunol. 2018;9:652.

[24] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.

[25] Wu D, Liu X, Mu J, Yang J, Wu F, Zhou H. Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers. Biomolecules. 2022;12(3):392.

[26] Fan QM, Jing YY, Yu GF, Kou XR, Ye F, Gao L, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2014;352(2):160–168.

[27] Raghavan S, Mehta P, Xie Y, Lei YL, Mehta G. Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments. J Immunother Cancer. 2019;7(1):190.

[28] Qiu SQ, Waaijer SJH, Zwager MC, de Vries EGE, van der Vegt B, Schroder CP. Tumor-associated macrophages in breast cancer: Innocent bystander or important player? Cancer Treat Rev. 2018;70:178–189.

[29] Choi J, Gyamfi J, Jang H, Koo JS. The role of tumor-associated macrophage in breast cancer biology. Histol Histopathol. 2018;33(2):133–145.

[30] Xiao M, He J, Yin L, Chen X, Zu X, Shen Y. Tumor-Associated Macrophages: Critical Players in Drug Resistance of Breast Cancer. Front Immunol. 2021;12:799428.

[31] Aharinejad S, Paulus P, Sioud M, Hofmann M, Zins K, Schäfer R, et al. Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res. 2004;64(15):5378–5384.

[32] Sangaletti S, Di Carlo E, Gariboldi S, Miotti S, Cappetti B, Parenza M, et al. Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis. Cancer Res. 2008;68(21):9050–9059.

[33] Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19(4):541–555.

[34] Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 2004;64(19):7022–7029.

[35] Kes MMG, Van den Bossche J, Griffioen AW, Huijbers EJM. Oncometabolites lactate and succinate drive pro-angiogenic macrophage response in tumors. Biochim Biophys Acta Rev Cancer. 2020;1874(2):188427.

[36] Nowak M, Klink M. The Role of Tumor-Associated Macrophages in the Progression and Chemoresistance of Ovarian Cancer. Cells. 2020;9(5):1299.

[37] Tong N, He Z, Ma Y, Wang Z, Huang Z, Cao H, et al. Tumor Associated Macrophages, as the Dominant Immune Cells, Are an Indispensable Target for Immunologically Cold Tumor-Glioma Therapy? Front Cell Dev Biol. 2021;9:706286.

[38] Zsiros E, Odunsi K. Tumor-associated macrophages: co-conspirators and orchestrators of immune suppression in endometrial adenocarcinoma. Gynecol Oncol. 2014;135(2):173–175.

[39] Kubler K, Ayub TH, Weber SK, Zivanovic O, Abramian A, Keyver-Paik MD, et al. Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma. Gynecol Oncol. 2014;135(2):176–183.

[40] Zou Z, Lin H, Li M, Lin B. Tumor-associated macrophage polarization in the inflammatory tumor microenvironment. Front Oncol. 2023;13:1103149.

[41] Ceci C, Atzori MG, Lacal PM, Graziani G. Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma. Cancers (Basel). 2020;12(11):3401.

[42] Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–949.

[43] Petty AJ, Li A, Wang X, Dai R, Heyman B, Hsu D, et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment. J Clin Invest. 2019;129(12):5151–5162.

[44] Zelenay S, van der Veen AG, Bottcher JP, Snelgrove KJ, Rogers N, Acton SE, et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell. 2015;162(6):1257–1270.

[45] Holt D, Ma X, Kundu N, Fulton A. Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4. Cancer Immunol Immunother. 2011;60(11):1577–1586.

[46] Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011;32(1):19–25.

[47] Gabrilovich DI, Bronte V, Chen S-H, Colombo MP, Ochoa A, Ostrand-Rosenberg S, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007;67(1):425.

[48] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–174.

[49] Perez C, Botta C, Zabaleta A, Puig N, Cedena M-T, Goicoechea I, et al. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma. Blood. 2020;136(2):199–209.

[50] Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008;111(8):4233–4244.

[51] Bronte V, Brandau S, Chen S-H, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.

[52] Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013;13(10):739–752.

[53] Wang D, Sun H, Wei J, Cen B, DuBois RN. CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer. Cancer Res. 2017;77(13):3655–3665.

[54] Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9(4):285–293.

[55] Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegué E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13(3):206–220.

[56] Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008;13(1):23–35.

[57] Madlambayan GJ, Butler JM, Hosaka K, Jorgensen M, Fu D, Guthrie SM, et al. Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger. Blood. 2009;114(19):4310–4319.

[58] Li B, Vincent A, Cates J, Brantley-Sieders DM, Polk DB, Young PP. Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res. 2009;69(1):338–348.

[59] Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6(4):409–421.

[60] Shah SC, Itzkowitz SH. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology. 2022;162(3):715–730.

[61] Shi G, Li D, Ren J, Li X, Wang T, Dou H, et al. mTOR inhibitor INK128 attenuates dextran sodium sulfate-induced colitis by promotion of MDSCs on Treg cell expansion. J Cell Physiol. 2019;234(2):1618–1629.

[62] Zhou J, Huang S, Wang Z, Huang J, Xu L, Tang X, et al. Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation. Nat Commun. 2019;10(1):2427.

[63] Ortiz ML, Kumar V, Martner A, Mony S, Donthireddy L, Condamine T, et al. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells. J Exp Med. 2015;212(3):351–367.

[64] Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer Immunol Res. 2017;5(1):3–8.

[65] Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485–498.

[66] Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukocyte Biol. 2015;98(6):913–22.

[67] Youn J-I, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. Journal of Immunology (Baltimore, Md : 1950). 2008;181(8):5791–5802.

[68] Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced Regulatory T Cells: Their Development, Stability, and Applications. Trends Immunol. 2016;37(11):803–811.

[69] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–336.

[70] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–1061.

[71] Feuerer M, Hill JA, Kretschmer K, von Boehmer H, Mathis D, Benoist C. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc Natl Acad Sci USA. 2010;107(13):5919–5924.

[72] Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature. 2013;501(7466):252–256.

[73] Qianmei Y, Zehong S, Guang W, Hui L, Lian G. Recent advances in the role of Th17/Treg cells in tumor immunity and tumor therapy. Immunol Res. 2021;69(5):398–414.

[74] Munn DH, Sharma MD, Johnson TS. Treg Destabilization and Reprogramming: Implications for Cancer Immunotherapy. Cancer Res. 2018;78(18):5191–5199.

[75] Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109–118.

[76] Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res. 2020;30(6):465–474.

[77] Zagorulya M, Yim L, Morgan DM, Edwards A, Torres-Mejia E, Momin N, et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity. 2023;56(2):386–405.e10.

[78] Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–275.

[79] Betts G, Twohig J, Van den Broek M, Sierro S, Godkin A, Gallimore A. The impact of regulatory T cells on carcinogen-induced sarcogenesis. Br J Cancer. 2007;96(12):1849–1854.

[80] Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475(7355):226–230.

[81] Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 2016;22(6):679–684.

[82] Koizumi SI, Sasaki D, Hsieh TH, Taira N, Arakaki N, Yamasaki S, et al. JunB regulates homeostasis and suppressive functions of effector regulatory T cells. Nat Commun. 2018;9(1):5344.

[83] Teh PP, Vasanthakumar A, Kallies A. Development and Function of Effector Regulatory T Cells. Prog Mol Biol Transl Sci. 2015;136:155–174.

[84] Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785–799.

[85] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–787.

[86] Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–2089.

[87] Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007;13(3):108–116.

[88] Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107(6):2409–2414.

[89] Wu H, Li P, Shao N, Ma J, Ji M, Sun X, et al. Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-beta in acute myeloid leukemia. Oncol Lett. 2012;3(5):1119–1123.

[90] Nicholl MB, Ledgewood CL, Chen X, Bai Q, Qin C, Cook KM, et al. IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: evidence for a role as an autocrine growth factor. Cytokine. 2014;70(2):126–133.

[91] Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007;27(4):635–646.

[92] Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, et al. PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA. 2019;116(20):9999–10008.

[93] De Simone V, Franzè E, Ronchetti G, Colantoni A, Fantini MC, Di Fusco D, et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene. 2015;34(27):3493–3503.

[94] Sharp SP, Avram D, Stain SC, Lee EC. Local and systemic Th17 immune response associated with advanced stage colon cancer. J Surg Res. 2017;208:180–186.

[95] Yan G, Liu T, Yin L, Kang Z, Wang L. Levels of peripheral Th17 cells and serum Th17-related cytokines in patients with colorectal cancer: a meta-analysis. Cell Mol Biol (Noisy-le-grand). 2018;64(6):94–102.

[96] Bos PD, Rudensky AY. Treg cells in cancer: a case of multiple personality disorder. Sci Transl Med. 2012;4(164):164fs44.

[97] Zhang Y, Lazarus J, Steele NG, Yan W, Lee H-J, Nwosu ZC, et al. Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis. Cancer Discov. 2020;10(3):422–439.

[98] Shang B, Liu Y, Jiang S-j, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.

[99] Poutahidis T, Haigis KM, Rao VP, Nambiar PR, Taylor CL, Ge Z, et al. Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma. Carcinogenesis. 2007;28(12):2614–2623.

[100] Tanaka A, Sakaguchi S. Targeting Treg cells in cancer immunotherapy. Eur J Immunol. 2019;49(8):1140–1146.

[101] Iglesias-Escudero M, Arias-González N, Martínez-Cáceres E. Regulatory cells and the effect of cancer immunotherapy. Mol Cancer. 2023;22(1):26.

[102] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999;163(10):5211–5218.

[103] Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA. 2008;105(29):10113–10118.

[104] Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B. 2020;10(3):414–433.

[105] Hombach S, Kretz M. Non-coding RNAs: Classification, Biology and Functioning. Adv Exp Med Biol. 2016;937:3–17.

[106] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297.

[107] Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105.

[108] Hutvágner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297(5589):2056–2060.

[109] Zeng Y, Cullen BR. Sequence requirements for micro RNA processing and function in human cells. RNA. 2003;9(1):112–123.

[110] Zeng Y, Yi R, Cullen BR. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA. 2003;100(17):9779–9784.

[111] Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet. 2015;16(7):421–433.

[112] Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, et al. Interplay between miRNAs and human diseases. J Cell Physiol. 2018;233(3):2007–2018.

[113] Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006;20(16):2202–2207.

[114] Iliou MS, da Silva-Diz V, Carmona FJ, Ramalho-Carvalho J, Heyn H, Villanueva A, et al. Impaired DICER1 function promotes stemness and metastasis in colon cancer. Oncogene. 2014;33(30):4003–4015.

[115] Al-Haidari AA, Syk I, Thorlacius H. MiR-155-5p positively regulates CCL17-induced colon cancer cell migration by targeting RhoA. Oncotarget. 2017;8(9):14887–14896.

[116] Chirshev E, Oberg KC, Ioffe YJ, Unternaehrer JJ. Let-7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer. Clin Transl Med. 2019;8(1):24.

[117] Alhasan L. MiR-126 Modulates Angiogenesis in Breast Cancer by Targeting VEGF-A -mRNA. Asian Pac J Cancer Prev. 2019;20(1):193–197.

[118] Chen SR, Cai WP, Dai XJ, Guo AS, Chen HP, Lin GS, et al. Research on miR-126 in glioma targeted regulation of PTEN/PI3K/Akt and MDM2-p53 pathways. Eur Rev Med Pharmacol Sci. 2019;23(8):3461–3470.

[119] Wang C, Tan S, Li J, Liu WR, Peng Y, Li W. CircRNAs in lung cancer - Biogenesis, function and clinical implication. Cancer Lett. 2020;492:106–115.

[120] Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics. 2013;193(3):651–669.

[121] Guo CJ, Xu G, Chen LL. Mechanisms of Long Noncoding RNA Nuclear Retention. Trends Biochem Sci. 2020;45(11):947–960.

[122] Wang Y, Li Z, Xu S, Li W, Chen M, Jiang M, et al. LncRNA FIRRE functions as a tumor promoter by interaction with PTBP1 to stabilize BECN1 mRNA and facilitate autophagy. Cell Death Dis. 2022;13(2):98.

[123] Qian G, Jin X, Zhang L. LncRNA FENDRR Upregulation Promotes Hepatic Carcinoma Cells Apoptosis by Targeting miR-362-5p Via NPR3 and p38-MAPK Pathway. Cancer Biother Radiopharm. 2020;35(9):629–639.

[124] Choudhari R, Sedano MJ, Harrison AL, Subramani R, Lin KY, Ramos EI, et al. Long noncoding RNAs in cancer: From discovery to therapeutic targets. Adv Clin Chem. 2020;95:105–147.

[125] Qin X, Lu M, Zhou Y, Li G, Liu Z. LncRNA FENDRR represses proliferation, migration and invasion through suppression of survivin in cholangiocarcinoma cells. Cell Cycle. 2019;18(8):889–897.

[126] Olivero CE, Martinez-Terroba E, Zimmer J, Liao C, Tesfaye E, Hooshdaran N, et al. p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis. Mol Cell. 2020;77(4):761–774 e8.

[127] Han X, Chen J, Wang J, Xu J, Liu Y. TTN mutations predict a poor prognosis in patients with thyroid cancer. Biosci Rep. 2022;42(7):BSR20221168.

[128] Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–338.

[129] Xiao MS, Ai Y, Wilusz JE. Biogenesis and Functions of Circular RNAs Come into Focus. Trends Cell Biol. 2020;30(3):226–240.

[130] Zhou WY, Cai ZR, Liu J, Wang DS, Ju HQ, Xu RH. Circular RNA: metabolism, functions and interactions with proteins. Mol Cancer. 2020;19(1):172.

[131] Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17(5):272–283.

[132] Panda AC. Circular RNAs Act as miRNA Sponges. Adv Exp Med Biol. 2018;1087:67–79.

[133] Liu Z, Zhou Y, Liang G, Ling Y, Tan W, Tan L, et al. Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p. Cell Death Dis. 2019;10(2):55.

[134] Huang XB, Song KJ, Chen GB, Liu R, Jiang ZF, He YL. Circular RNA hsa_circ_0003204 promotes cervical cancer cell proliferation, migration, and invasion by regulating MAPK pathway. Cancer Biol Ther. 2020;21(10):972–982.

[135] Guo Y, Guo Y, Chen C, Fan D, Wu X, Zhao L, et al. Circ3823 contributes to growth, metastasis and angiogenesis of colorectal cancer: involvement of miR-30c-5p/TCF7 axis. Mol Cancer. 2021;20(1):93.

[136] Zhang PF, Gao C, Huang XY, Lu JC, Guo XJ, Shi GM, et al. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer. 2020;19(1):110.

[137] Wu J, Chen Z, Song Y, Zhu Y, Dou G, Shen X, et al. CircRNA_0005075 suppresses carcinogenesis via regulating miR-431/p53/epithelial-mesenchymal transition axis in gastric cancer. Cell Biochem Funct. 2020;38(7):932–942.

[138] Audia JE, Campbell RM. Histone Modifications and Cancer. Cold Spring Harb Perspect Biol. 2016;8(4):a019521.

[139] Bowman GD, Poirier MG. Post-translational modifications of histones that influence nucleosome dynamics. Chem Rev. 2015;115(6):2274–2295.

[140] Zhang Y, Sun Z, Jia J, Du T, Zhang N, Tang Y, et al. Overview of Histone Modification. Adv Exp Med Biol. 2021;1283:1–16.

[141] Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications. Cell. 2000;103(2):263–271.

[142] Loomis RJ, Naoe Y, Parker JB, Savic V, Bozovsky MR, Macfarlan T, et al. Chromatin binding of SRp20 and ASF/SF2 and dissociation from mitotic chromosomes is modulated by histone H3 serine 10 phosphorylation. Mol Cell. 2009;33(4):450–461.

[143] Wang K, Liu H, Hu Q, Wang L, Liu J, Zheng Z, et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct Target Ther. 2022;7(1):374.

[144] Solier S, Pommier Y. The apoptotic ring: a novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases. Cell Cycle. 2009;8(12):1853–1859.

[145] Xu J, Richard S. Cellular pathways influenced by protein arginine methylation: Implications for cancer. Mol Cell. 2021;81(21):4357–4368.

[146] Mori F, Natali L, Danesi R, Nannizzi S, Farina C. Post-translational modifications and antioxidant properties of different therapeutic human serum albumins. Int J Biol Macromol. 2021;183:927–935.

[147] Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13(5):343–357.

[148] Zhang X, Wen H, Shi X. Lysine methylation: beyond histones. Acta Biochim Biophy Sin. 2012;44(1):14–27.

[149] Shen Y, Wei W, Zhou DX. Histone Acetylation Enzymes Coordinate Metabolism and Gene Expression. Trends Plant Sci. 2015;20(10):614–621.

[150] Ellinger J, Kahl P, Mertens C, Rogenhofer S, Hauser S, Hartmann W, et al. Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int J Cancer. 2010;127(10):2360–2366.

[151] Barlési F, Giaccone G, Gallegos-Ruiz MI, Loundou A, Span SW, Lefesvre P, et al. Global histone modifications predict prognosis of resected non small-cell lung cancer. J Clin Oncol. 2007;25(28):4358–4364.

[152] Liu YX, Li QZ, Cao YN, Zhang LQ. Identification of key genes and important histone modifications in hepatocellular carcinoma. Comput Struct Biotechnol J. 2020;18:2657–2669.

[153] Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM, et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 2009;69(9):3802–3809.

[154] Amin SA, Khatun S, Gayen S, Das S, Jha T. Are inhibitors of histone deacetylase 8 (HDAC8) effective in hematological cancers especially acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)? Eur J Med Chem. 2023;258:115594.

[155] Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–492.

[156] Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19(2):81–92.

[157] Jones PA, Liang G. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009;10(11):805–811.

[158] Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502(7472):472–479.

[159] Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517–534.

[160] Zhang MW, Fujiwara K, Che X, Zheng S, Zheng L. DNA methylation in the tumor microenvironment. J Zhejiang Univ Sci B. 2017;18(5):365–372.

[161] Janson PCJ, Marits P, Thörn M, Ohlsson R, Winqvist O. CpG methylation of the IFNG gene as a mechanism to induce immunosuppression in tumor-infiltrating lymphocytes. J Immunol. 2008;181(4):2878–2886.

[162] Jung H, Kim HS, Kim JY, Sun JM, Ahn JS, Ahn MJ, et al. DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load. Nat Commun. 2019;10(1):4278.

[163] Hogg SJ, Beavis PA, Dawson MA, Johnstone RW. Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discov. 2020;19(11):776–800.

[164] Cao J, Yan Q. Cancer Epigenetics, Tumor Immunity, and Immunotherapy. Trends Cancer. 2020;6(7):580–592.

[165] Dai E, Zhu Z, Wahed S, Qu Z, Storkus WJ, Guo ZS. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer. 2021;20(1):171.

[166] Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone Deacetylase Inhibitors as Anticancer Drugs. Int J Mol Sci. 2017;18(7):1414.

[167] Ford BR, Vignali PDA, Rittenhouse NL, Scharping NE, Peralta R, Lontos K, et al. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci Immunol. 2022;7(74):eabj9123.

[168] Sim W, Lim WM, Hii LW, Leong CO, Mai CW. Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases. World J Gastroenterol. 2022;28(18):1934–1945.

[169] Ding P, Ma Z, Liu D, Pan M, Li H, Feng Y, et al. Lysine Acetylation/Deacetylation Modification of Immune-Related Molecules in Cancer Immunotherapy. Front Immunol. 2022;13:865975.

[170] Zhou Z, Wang Z, Gao J, Lin Z, Wang Y, Shan P, et al. Noncoding RNA-mediated macrophage and cancer cell crosstalk in hepatocellular carcinoma. Mol Ther Oncolytics. 2022;25:98–120.

[171] Zhou SL, Hu ZQ, Zhou ZJ, Dai Z, Wang Z, Cao Y, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology. 2016;63(5):1560–1575.

[172] Zhao J, Li H, Zhao S, Wang E, Zhu J, Feng D, et al. Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling. Mol Cancer. 2021;20(1):46.

[173] Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13(1):156.

[174] Zheng P, Chen L, Yuan X, Luo Q, Liu Y, Xie G, et al. Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J Exp Clin Cancer Res. 2017;36(1):53.

[175] Yu X, Li R, Shi W, Jiang T, Wang Y, Li C, et al. Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells. Biomed Pharmacother. 2016;77:37–44.

[176] Zhou H, Gan M, Jin X, Dai M, Wang Y, Lei Y, et al. miR382 inhibits breast cancer progression and metastasis by affecting the M2 polarization of tumorassociated macrophages by targeting PGC1alpha. Int J Oncol. 2022;61(4):126.

[177] Zhang X, Wang J, Liu N, Wu W, Li H, Chen J, et al. Molecular mechanism of CD163(+) tumor-associated macrophage (TAM)-derived exosome-induced cisplatin resistance in ovarian cancer ascites. Ann Transl Med. 2022;10(18):1014.

[178] Zhu X, Shen H, Yin X, Yang M, Wei H, Chen Q, et al. Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype. J Exp Clin Cancer Res. 2019;38(1):81.

[179] Yin Z, Ma T, Huang B, Lin L, Zhou Y, Yan J, et al. Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-beta signaling pathway. J Exp Clin Cancer Res. 2019;38(1):310.

[180] Guan H, Peng R, Fang F, Mao L, Chen Z, Yang S, et al. Tumor-associated macrophages promote prostate cancer progression via exosome-mediated miR-95 transfer. J Cell Physiol. 2020;235(12):9729–9742.

[181] Wang Y, Wang B, Xiao S, Li Y, Chen Q. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem. 2019;120(3):3046–3055.

[182] Xie T, Fu DJ, Li ZM, Lv DJ, Song XL, Yu YZ, et al. Circ-SMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling. Mol Cancer. 2022;21(1):173.

[183] Zhu M, Zhu Z, Jiang P, Zheng J, Yan F, Feng J. CircMERTK modulates the suppressive capacity of tumor-associated macrophage via targeting IL-10 in colorectal cancer. Hum Cell. 2022;36(1):276–285.

[184] Hu ZQ, Zhou SL, Li J, Zhou ZJ, Wang PC, Xin HY, et al. Circular RNA Sequencing Identifies CircASAP1 as a Key Regulator in Hepatocellular Carcinoma Metastasis. Hepatology. 2020;72(3):906–922.

[185] Lu Q, Wang X, Zhu J, Fei X, Chen H, Li C. Hypoxic Tumor-Derived Exosomal Circ0048117 Facilitates M2 Macrophage Polarization Acting as miR-140 Sponge in Esophageal Squamous Cell Carcinoma. Onco Targets Ther. 2020;13:11883–11897.

[186] Pan Z, Zhao R, Li B, Qi Y, Qiu W, Guo Q, et al. EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Mol Cancer. 2022;21(1):16.

[187] Chen T, Liu Y, Li C, Xu C, Ding C, Chen J, et al. Tumor-derived exosomal circFARSA mediates M2 macrophage polarization via the PTEN/PI3K/AKT pathway to promote non-small cell lung cancer metastasis. Cancer Treat Res Commun. 2021;28:100412.

[188] Lai F, Zhang H, Xu B, Xie Y, Yu H. Long non-coding RNA NBR2 suppresses the progress of colorectal cancer in vitro and in vivo by regulating the polarization of TAM. Bioengineered. 2021;12(1):5462–5475.

[189] Zhou L, Tian Y, Guo F, Yu B, Li J, Xu H, et al. LincRNA-p21 knockdown reversed tumor-associated macrophages function by promoting MDM2 to antagonize* p53 activation and alleviate breast cancer development. Cancer Immunol Immunother. 2020;69(5):835–846.

[190] Zhao Y, Yu Z, Ma R, Zhang Y, Zhao L, Yan Y, et al. lncRNA-Xist/miR-101-3p/KLF6/C/EBPalpha axis promotes TAM polarization to regulate cancer cell proliferation and migration. Mol Ther Nucleic Acids. 2021;23:536–551.

[191] Zong S, Dai W, Guo X, Wang K. LncRNA-SNHG1 promotes macrophage M2-like polarization and contributes to breast cancer growth and metastasis. Aging (Albany NY). 2021;13(19):23169–23181.

[192] Tu J, Tan X, Chen Y, Chen Y, Li Z, Zhang Y, et al. Growth arrest-specific transcript 5 represses endometrial cancer development by promoting antitumor function of tumor-associated macrophages. Cancer Sci. 2022;113(8):2496–2512.

[193] Xin L, Zhou LQ, Liu C, Zeng F, Yuan YW, Zhou Q, et al. Transfer of LncRNA CRNDE in TAM-derived exosomes is linked with cisplatin resistance in gastric cancer. EMBO Rep. 2021;22(12):e52124.

[194] Guo Y, Li Z, Sun W, Gao W, Liang Y, Mei Z, et al. M2 Tumor Associate Macrophage- (TAM-) Derived lncRNA HISLA Promotes EMT Potential in Bladder Cancer. J Oncol. 2022;2022:1–13.

[195] Liu Y, Shi M, He X, Cao Y, Liu P, Li F, et al. LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma. J Hematol Oncol. 2022;15(1):52.

[196] Liu Y, Wang X, Zhu Y, Cao Y, Wang L, Li F, et al. The CTCF/LncRNA-PACERR complex recruits E1A binding protein p300 to induce pro-tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression. Clin Transl Med. 2022;12(2):e654.

[197] Yang D, Liu K, Fan L, Liang W, Xu T, Jiang W, et al. LncRNA RP11-361F15.2 promotes osteosarcoma tumorigenesis by inhibiting M2-Like polarization of tumor-associated macrophages of CPEB4. Cancer Lett. 2020;473:33–49.

[198] Hall JR, Messenger ZJ, Tam HW, Phillips SL, Recio L, Smart RC. Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes. Cell Death Dis. 2015;6(3):e1700.

[199] Nandi B, Shapiro M, Samur MK, Pai C, Frank NY, Yoon C, et al. Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages. Oncoimmunology. 2016;5(8):e1189052.

[200] Zhu M, Zhu Z, Jiang P, Zheng J, Yan F, Feng J. CircMERTK modulates the suppressive capacity of tumor-associated macrophage via targeting IL-10 in colorectal cancer. Hum Cell. 2023;36(1):276–285.

[201] Nakajima S, Mimura K, Saito K, Thar Min AK, Endo E, Yamada L, et al. Neoadjuvant Chemotherapy Induces IL34 Signaling and Promotes Chemoresistance via Tumor-Associated Macrophage Polarization in Esophageal Squamous Cell Carcinoma. Molecular Cancer Research : MCR. 2021;19(6):1085–1095.

[202] Zhao Y, Yu Z, Ma R, Zhang Y, Zhao L, Yan Y, et al. lncRNA-Xist/miR-101-3p/KLF6/C/EBPα axis promotes TAM polarization to regulate cancer cell proliferation and migration. Mol Ther Nucleic Acids. 2021;23:536–551.

[203] Choi W, Lee J, Lee J, Lee SH, Kim S. Hepatocyte Growth Factor Regulates Macrophage Transition to the M2 Phenotype and Promotes Murine Skeletal Muscle Regeneration. Frontiers In Physiology. 2019;10:914.

[204] Xu Z, Chen Y, Ma L, Chen Y, Liu J, Guo Y, et al. Role of exosomal non-coding RNAs from tumor cells and tumor-associated macrophages in the tumor microenvironment. Mol Ther. 2022;30(10):3133–3154.

[205] Lu L, Ling W, Ruan Z. TAM-derived extracellular vesicles containing microRNA-29a-3p explain the deterioration of ovarian cancer. Mol Ther Nucleic Acids. 2021;25:468–482.

[206] Yuan M, Wang Y, Sun Q, Liu S, Xian S, Dai F, et al. Identification of a Nine Immune-Related lncRNA Signature as a Novel Diagnostic Biomarker for Hepatocellular Carcinoma. Biomed Res Int. 2021;2021:9798231.

[207] Xu E, Hu M, Ge R, Tong D, Fan Y, Ren X, et al. LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells. Front Vet Sci. 2021;8:654694.

[208] Ge Y, Tu W, Li J, Chen X, Chen Y, Xu Y, et al. MiR-122-5p increases radiosensitivity and aggravates radiation-induced rectal injury through CCAR1. Toxicol Appl Pharmacol. 2020;399:115054.

[209] Abdollahi E, Mozdarani H, Alizadeh BZ. Role of circ-FOXO3 and miR-23a in radiosensitivity of breast cancer. Breast Cancer. 2023;30(5):714–726.

[210] Raguram A, Banskota S, Liu DR. Therapeutic in vivo delivery of gene editing agents. Cell. 2022;185(15):2806–2827.

[211] Du J, Fan JJ, Dong C, Li HT, Ma BL. Inhibition effect of exosomes-mediated Let-7a on the development and metastasis of triple negative breast cancer by down-regulating the expression of c-Myc. Eur Rev Med Pharmacol Sci. 2019;23(12):5301–5314.

[212] Naseri Z, Oskuee RK, Forouzandeh-Moghadam M, Jaafari MR. Delivery of LNA-antimiR-142-3p by Mesenchymal Stem Cells-Derived Exosomes to Breast Cancer Stem Cells Reduces Tumorigenicity. Stem Cell Reviews and Reports. 2020;16(3):541–556.

[213] Toriyabe N, Sakurai Y, Kato A, Yamamoto S, Tange K, Nakai Y, et al. The Delivery of Small Interfering RNA to Hepatic Stellate Cells Using a Lipid Nanoparticle Composed of a Vitamin A-Scaffold Lipid-Like Material. J Pharm Sci. 2017;106(8):2046–2052.

[214] Zhu J, Yang S, Qi Y, Gong Z, Zhang H, Liang K, et al. Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. Sci Adv. 2022;8(13):eabk0011.

[215] Zhang C, Wang S, Liu Y, Yang C. Epigenetics in myeloid derived suppressor cells: a sheathed sword towards cancer. Oncotarget. 2016;7(35):57452–57463.

[216] Zhang M, Liu Q, Mi S, Liang X, Zhang Z, Su X, et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J Immunol. 2011;186(8):4716–4724.

[217] Noman MZ, Janji B, Hu S, Wu JC, Martelli F, Bronte V, et al. Tumor-Promoting Effects of Myeloid-Derived Suppressor Cells Are Potentiated by Hypoxia-Induced Expression of miR-210. Cancer Res. 2015;75(18):3771–3787.

[218] Tian J, Rui K, Tang X, Ma J, Wang Y, Tian X, et al. MicroRNA-9 Regulates the Differentiation and Function of Myeloid-Derived Suppressor Cells via Targeting Runx1. J Immunol. 2015;195(3):1301–1311.

[219] Zhang X, Li F, Tang Y, Ren Q, Xiao B, Wan Y, et al. miR-21a in exosomes from Lewis lung carcinoma cells accelerates tumor growth through targeting PDCD4 to enhance expansion of myeloid-derived suppressor cells. Oncogene. 2020;39(40):6354–6369.

[220] Wang X, Chang X, Zhuo G, Sun M, Yin K. Twist and miR-34a are involved in the generation of tumor-educated myeloid-derived suppressor cells. Int J Mol Sci. 2013;14(10):20459–20477.

[221] Wang J, Yu F, Jia X, Iwanowycz S, Wang Y, Huang S, et al. MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth. Int J Cancer. 2015;136(6):E602–E613.

[222] Zhao Q, Huang L, Qin G, Qiao Y, Ren F, Shen C, et al. Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma. Cancer Lett. 2021;518:35–48.

[223] Li L, Zhang J, Diao W, Wang D, Wei Y, Zhang CY, et al. MicroRNA-155 and MicroRNA-21 promote the expansion of functional myeloid-derived suppressor cells. J Immunol. 2014;192(3):1034–1043.

[224] Qiu W, Guo X, Li B, Wang J, Qi Y, Chen Z, et al. Exosomal miR-1246 from glioma patient body fluids drives the differentiation and activation of myeloid-derived suppressor cells. Mol Ther. 2021;29(12):3449–3464.

[225] Zhou JH, Yao ZX, Zheng Z, Yang J, Wang R, Fu SJ, et al. G-MDSCs-Derived Exosomal miRNA-143-3p Promotes Proliferation via Targeting of ITM2B in Lung Cancer. Onco Targets Ther. 2020;13:9701–9719.

[226] Gao F, Xu Q, Tang Z, Zhang N, Huang Y, Li Z, et al. Exosomes derived from myeloid-derived suppressor cells facilitate castration-resistant prostate cancer progression via S100A9/circMID1/miR-506-3p/MID1. J Transl Med. 2022;20(1):346.

[227] Tian X, Ma J, Wang T, Tian J, Zhang Y, Mao L, et al. Long Non-Coding RNA HOXA Transcript Antisense RNA Myeloid-Specific 1-HOXA1 Axis Downregulates the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in Lung Cancer. Front Immunol. 2018;9:473.

[228] Zhou Q, Tang X, Tian X, Tian J, Zhang Y, Ma J, et al. LncRNA MALAT1 negatively regulates MDSCs in patients with lung cancer. J Cancer. 2018;9(14):2436–2442.

[229] Tian X, Ma J, Wang T, Tian J, Zheng Y, Peng R, et al. Long non-coding RNA RUNXOR accelerates MDSC-mediated immunosuppression in lung cancer. BMC Cancer. 2018;18(1):660.

[230] Zheng Y, Tian X, Wang T, Xia X, Cao F, Tian J, et al. Long noncoding RNA Pvt1 regulates the immunosuppression activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. Mol Cancer. 2019;18(1):61.

[231] Tian X, Zheng Y, Yin K, Ma J, Tian J, Zhang Y, et al. LncRNA AK036396 Inhibits Maturation and Accelerates Immunosuppression of Polymorphonuclear Myeloid-Derived Suppressor Cells by Enhancing the Stability of Ficolin B. Cancer Immunol Res. 2020;8(4):565–577.

[232] Gao Y, Sun W, Shang W, Li Y, Zhang D, Wang T, et al. Lnc-C/EBPbeta Negatively Regulates the Suppressive Function of Myeloid-Derived Suppressor Cells. Cancer Immunol Res. 2018;6(11):1352–1363.

[233] Gao Y, Shang W, Zhang D, Zhang S, Zhang X, Zhang Y, et al. Lnc-C/EBPbeta Modulates Differentiation of MDSCs Through Downregulating IL4i1 With C/EBPbeta LIP and WDR5. Front Immunol. 2019;10:1661.

[234] Shan K, Li CP, Liu C, Liu X, Yan B. RNCR3: A regulator of diabetes mellitus-related retinal microvascular dysfunction. Biochem Biophys Res Commun. 2017;482(4):777–783.

[235] Yu H, Chen C, Han F, Tang J, Deng M, Niu Y, et al. Long Noncoding RNA MIR4435-2HG Suppresses Colorectal Cancer Initiation and Progression By Reprogramming Neutrophils. Cancer Immunol Res. 2022;10(9):1095–1110.

[236] Zhou L, Park JJ, Zheng Q, Dong Z, Mi Q. MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cell Mol Immunol. 2011;8(5):380–387.

[237] Yao R, Ma YL, Liang W, Li HH, Ma ZJ, Yu X, et al. MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS One. 2012;7(10):e46082.

[238] Zhang Y, Wang ZC, Zhang ZS, Chen F. MicroRNA-155 regulates cervical cancer via inducing Th17/Treg imbalance. Eur Rev Med Pharmacol Sci. 2018;22(12):3719–3726.

[239] Zheng X, Dong L, Wang K, Zou H, Zhao S, Wang Y, et al. MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection. Ann Surg Oncol. 2019;26(3):884–893.

[240] Yu Z, Zhao H, Feng X, Li H, Qiu C, Yi X, et al. Long Non-coding RNA FENDRR Acts as a miR-423-5p Sponge to Suppress the Treg-Mediated Immune Escape of Hepatocellular Carcinoma Cells. Mol Ther Nucleic Acids. 2019;17:516–529.

[241] Wu D, Tang R, Qi Q, Zhou X, Zhou H, Mao Y, et al. Five functional polymorphisms of B7/CD28 co-signaling molecules alter susceptibility to colorectal cancer. Cell Immunol. 2015;293(1):41–48.

[242] Zheng Z, Xu PP, Wang L, Zhao HJ, Weng XQ, Zhong HJ, et al. MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells. J Exp Clin Cancer Res. 2017;36(1):82.

[243] Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J, et al. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res. 2014;24(10):1164–1180.

[244] Ye SB, Zhang H, Cai TT, Liu YN, Ni JJ, He J, et al. Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol. 2016;240(3):329–340.

[245] Huang M, Huang X, Huang N. Exosomal circGSE1 promotes immune escape of hepatocellular carcinoma by inducing the expansion of regulatory T cells. Cancer Sci. 2022;113(6):1968–1983.

[246] Chen Y, Li Z, Liang J, Liu J, Hao J, Wan Q, et al. CircRNA has_circ_0069313 induced OSCC immunity escape by miR-325-3p-Foxp3 axes in both OSCC cells and Treg cells. Aging (Albany NY). 2022;14(10):4376–4389.

[247] Xiaoli T, Wenting W, Meixiang Z, Chunlei Z, Chengxia H. Long Noncoding RNA RP11-357H14.17 Plays an Oncogene Role in Gastric Cancer by Activating ATF2 Signaling and Enhancing Treg Cells. Biomed Res Int. 2021;2021:6635936.

[248] Xiong G, Yang L, Chen Y, Fan Z. Linc-POU3F3 promotes cell proliferation in gastric cancer via increasing T-reg distribution. Am J Transl Res. 2015;7(11):2262–2269.

[249] Fan Y, Gao Y, Rao J, Wang K, Zhang F, Zhang C. YAP-1 Promotes Tregs Differentiation in Hepatocellular Carcinoma by Enhancing TGFBR2 Transcription. Cell Physiol Biochem. 2017;41(3):1189–1198.

[250] Wang J, Huang F, Shi Y, Zhang Q, Xu S, Yao Y, et al. RP11-323N12.5 promotes the malignancy and immunosuppression of human gastric cancer by increasing YAP1 transcription. Gastric Cancer. 2021;24(1):85–102.

[251] Ni C, Fang QQ, Chen WZ, Jiang JX, Jiang Z, Ye J, et al. Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+gammadelta1 Treg cells. Signal Transduct Target Ther. 2020;5(1):41.

[252] Zhong C, Tao B, Li X, Xiang W, Peng L, Peng T, et al. HOXA-AS2 contributes to regulatory T cell proliferation and immune tolerance in glioma through the miR-302a/KDM2A/JAG1 axis. Cell Death Dis. 2022;13(2):160.

[253] Zhou J, Li X, Wu X, Zhang T, Zhu Q, Wang X, et al. Exosomes Released from Tumor-Associated Macrophages Transfer miRNAs That Induce a Treg/Th17 Cell Imbalance in Epithelial Ovarian Cancer. Cancer Immunol Res. 2018;6(12):1578–1592.

[254] Meredith RF, Buchsbaum DJ, Alvarez RD, LoBuglio AF. Brief overview of preclinical and clinical studies in the development of intraperitoneal radioimmunotherapy for ovarian cancer. Clin Cancer Res. 2007;13(18 Pt 2):5643s–5645s.

[255] Xu L, Zhou C, Liang Y, Fan T, Zhang F, Chen X, et al. Epigenetic modifications in the accumulation and function of myeloid-derived suppressor cells. Front Immunol. 2022;13:1016870.

[256] Tian X, Wang T, Shen H, Wang S. Tumor microenvironment, histone modifications, and myeloid-derived suppressor cells. Cytokine Growth Factor Rev. 2023;74:108–121.

[257] Sasidharan Nair V, Saleh R, Toor SM, Taha RZ, Ahmed AA, Kurer MA, et al. Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer. Clin Epigenetics. 2020;12(1):13.

[258] Redd PS, Ibrahim ML, Klement JD, Sharman SK, Paschall AV, Yang D, et al. SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells. Cancer Res. 2017;77(11):2834–2843.

[259] Lu C, Liu Z, Klement JD, Yang D, Merting AD, Poschel D, et al. WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape. J Immunother Cancer. 2021;9(7):e002624.

[260] Wang HF, Ning F, Liu ZC, Wu L, Li ZQ, Qi YF, et al. Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro. Cancer Immunol Immunother. 2017;66(3):355–366.

[261] Kim YD, Park SM, Ha HC, Lee AR, Won H, Cha H, et al. HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment. J Cancer. 2020;11(14):4059–4072.

[262] Stone ML, Chiappinelli KB, Li H, Murphy LM, Travers ME, Topper MJ, et al. Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc Natl Acad Sci U S A. 2017;114(51):E10981–e10990.

[263] Liu Y, Bao C, Wang L, Han R, Beier UH, Akimova T, et al. Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells. Cancers (Basel). 2019;11(4):554.

[264] de Jong A, de Jong RCM, Peters EA, Arens R, Jukema JW, de Vries MR, et al. P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells. Front Cardiovasc Med. 2020;7:604821.

[265] Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007;13(11):1299–1307.

[266] Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One. 2012;7(1):e30815.

[267] Bastian L, Hof J, Pfau M, Fichtner I, Eckert C, Henze G, et al. Synergistic activity of bortezomib and HDACi in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT, and NF-κB. Clin Cancer Res. 2013;19(6):1445–1457.

[268] Buchwald M, Krämer OH, Heinzel T. HDACi–targets beyond chromatin. Cancer Lett. 2009;280(2):160–167.

[269] Parveen R, Harihar D, Chatterji BP. Recent histone deacetylase inhibitors in cancer therapy. Cancer. 2023;129(21):3372–3380.

[270] Cheshmazar N, Hamzeh-Mivehroud M, Nozad Charoudeh H, Hemmati S, Melesina J, Dastmalchi S. Current trends in development of HDAC-based chemotherapeutics. Life Sci. 2022;308:120946.

[271] Stone ML, Chiappinelli KB, Li H, Murphy LM, Travers ME, Topper MJ, et al. Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc Nat Acad Sci USA. 2017;114(51):E10981–E10990.

[272] Travers M, Brown SM, Dunworth M, Holbert CE, Wiehagen KR, Bachman KE, et al. DFMO and 5-Azacytidine Increase M1 Macrophages in the Tumor Microenvironment of Murine Ovarian Cancer. Cancer Res. 2019;79(13):3445–3454.

[273] Pan W, Zhu S, Qu K, Meeth K, Cheng J, He K, et al. The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression. Immunity. 2017;47(2):284–297.

[274] Cheng C, Huang C, Ma T-T, Bian E-B, He Y, Zhang L, et al. SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide-induced inflammatory cytokines in macrophages. Toxicol Lett. 2014;225(3):488–497.

[275] Tang R-Z, Zhu J-J, Yang F-F, Zhang Y-P, Xie S-A, Liu Y-F, et al. DNA methyltransferase 1 and Krüppel-like factor 4 axis regulates macrophage inflammation and atherosclerosis. J Mol Cell Cardiol. 2019;128:11–24.

[276] Yang X, Wang X, Liu D, Yu L, Xue B, Shi H. Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Molecular Endocrinology (Baltimore, Md). 2014;28(4):565–574.

[277] Saleh R, Toor SM, Taha RZ, Al-Ali D, Sasidharan Nair V, Elkord E. DNA methylation in the promoters of PD-L1, MMP9, ARG1, galectin-9, TIM-3, VISTA and TGF-β genes in HLA-DR myeloid cells, compared with HLA-DR antigen-presenting cells. Epigenetics. 2020;15(12):1275–1288.

[278] Sasidharan Nair V, Saleh R, Toor SM, Taha RZ, Ahmed AA, Kurer MA, et al. Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer. Clinical Epigenetics. 2020;12(1):13.

[279] Rodríguez-Ubreva J, Català-Moll F, Obermajer N, Álvarez-Errico D, Ramirez RN, Company C, et al. Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells. Cell Rep. 2017;21(1):154–167.

[280] Sido JM, Yang X, Nagarkatti PS, Nagarkatti M. Δ9-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid-derived suppressor cell activation via STAT3/S100A8. J Leukocyte Biol. 2015;97(4):677–688.

[281] Moorman HR, Reategui Y, Poschel DB, Liu K. IRF8: Mechanism of Action and Health Implications. Cells. 2022;11(17):2630.

[282] Ai L, Mu S, Sun C, Fan F, Yan H, Qin Y, et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol Cancer. 2019;18(1):88.

[283] Ibrahim ML, Klement JD, Lu C, Redd PS, Xiao W, Yang D, et al. Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis. Cell Rep. 2018;25(11):3036–3046.

[284] Linchong Sun HZ, Ping Gao. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell. 2022;13(12):877–919.

[285] Zhou J, Yao Y, Shen Q, Li G, Hu L, Zhang X. Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells. J Cancer Res Clin Oncol. 2017;143(8):1371–1380.

[286] Daurkin I, Eruslanov E, Vieweg J, Kusmartsev S. Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2'-deoxycytidine. Cancer Immunology, Immunotherapy : CII. 2010;59(5):697–706.

[287] Gius D, Cui H, Bradbury CM, Cook J, Smart DK, Zhao S, et al. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell. 2004;6(4):361–371.

[288] Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity. 2001;15(5):763–74.

[289] Polansky JK, Schreiber L, Thelemann C, Ludwig L, Krüger M, Baumgrass R, et al. Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. Journal of Molecular Medicine (Berlin, Germany). 2010;88(10):1029–1040.

[290] Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785–799.

[291] Yue X, Lio C-WJ, Samaniego-Castruita D, Li X, Rao A. Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nat Commun. 2019;10(1):2011.

[292] Yue X, Trifari S, Äijö T, Tsagaratou A, Pastor WA, Zepeda-Martínez JA, et al. Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016;213(3):377–397.

[293] Yue X, Samaniego-Castruita D, González-Avalos E, Li X, Barwick BG, Rao A. Whole-genome analysis of TET dioxygenase function in regulatory T cells. EMBO Rep. 2021;22(8):e52716.

[294] Tseng W-Y, Huang Y-S, Clanchy F, McNamee K, Perocheau D, Ogbechi J, et al. TNF receptor 2 signaling prevents DNA methylation at the promoter and prevents pathogenic conversion of regulatory T cells. Proc Nat Acad Sci USA. 2019;116(43):21666–21672.

[295] Samanta A, Li B, Song X, Bembas K, Zhang G, Katsumata M, et al. TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc Nat Acad Sci USA. 2008;105(37):14023–14027.

[296] Doganci A, Sauer K, Karwot R, Finotto S. Pathological role of IL-6 in the experimental allergic bronchial asthma in mice. Clin Rev Allergy Immunol. 2005;28(3):257–270.

[297] Wang L, Liu Y, Beier UH, Han R, Bhatti TR, Akimova T, et al. Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood. 2013;121(18):3631–3639.

[298] Qiao J, Wang Y, Li X, Jiang F, Zhang Y, Ma J, et al. A Lancet Commission on 70 years of women's reproductive, maternal, newborn, child, and adolescent health in China. Lancet. 2021;397(10293):2497–2536.

[299] Khong T, Sharkey J, Spencer A. The effect of azacitidine on interleukin-6 signaling and nuclear factor-kappaB activation and its in vitro and in vivo activity against multiple myeloma. Haematologica. 2008;93(6):860–869.

[300] 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(5):974–986.

[301] Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell. 2015;162(5):961–973.

[302] Issa J-PJ, Kantarjian HM. Targeting DNA methylation. Clinical Cancer Research : an Official Journal of the American Association For Cancer Research. 2009;15(12):3938–3946.

[303] Shang D, Li G, Zhang C, Liu Y. Synergistic inhibitory effects of 5-aza-2'-deoxycytidine and cisplatin on urothelial carcinoma growth via suppression of TGFBI-MAPK signaling pathways. Biochem Cell Biol. 2022;100(2):115–124.

[304] Pan B, Yin S, Peng F, Liu C, Liang H, Su J, et al. Vorinostat targets UBE2C to reverse epithelial-mesenchymal transition and control cervical cancer growth through the ubiquitination pathway. Eur J Pharmacol. 2021;908:174399.

[305] Xia C, He Z, Cai Y, Liang S. Vorinostat upregulates MICA via the PI3K/Akt pathway to enhance the ability of natural killer cells to kill tumor cells. Eur J Pharmacol. 2020;875:173057.

[306] Duan H, Heckman CA, Boxer LM. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol. 2005;25(5):1608–1019.

[307] Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P, et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med. 2005;11(1):77–84.

[308] Zhang Y, Adachi M, Kawamura R, Imai K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ. 2006;13(1):129–140.

[309] Makena MR, Ko M, Dang DK, Rao R. Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells. Cancers. 2021;13(2):259.

[310] Valdez BC, Brammer JE, Li Y, Murray D, Liu Y, Hosing C, et al. Romidepsin targets multiple survival signaling pathways in malignant T cells. Blood Cancer J. 2015;5(10):e357.

[311] Salmon JM, Todorovski I, Stanley KL, Bruedigam C, Kearney CJ, Martelotto LG, et al. Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML. Cancer Discov. 2022;12(6):1560–1579.

[312] Schmitz RL, Weissbach J, Kleilein J, Bell J, Hüttelmaier S, Viol F, et al. Targeting HDACs in Pancreatic Neuroendocrine Tumor Models. Cells. 2021;10(6):1408.

[313] Lee N-R, Kim D-Y, Jin H, Meng R, Chae OH, Kim S-H, et al. Inactivation of the Akt/FOXM1 Signaling Pathway by Panobinostat Suppresses the Proliferation and Metastasis of Gastric Cancer Cells. Int J Mol Sci. 2021;22(11):5955.

[314] Qin G, Li Y, Xu X, Wang X, Zhang K, Tang Y, et al. Panobinostat (LBH589) inhibits Wnt/β-catenin signaling pathway via upregulating APCL expression in breast cancer. Cell Signalling. 2019;59:62–75.

[315] Xi M, Guo S, Bayin C, Peng L, Chuffart F, Bourova-Flin E, et al. Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia. Frontiers of Medicine. 2022;16(3):442–458.

[316] Ding N, You A, Tian W, Gu L, Deng D. Chidamide increases the sensitivity of Non-small Cell Lung Cancer to Crizotinib by decreasing c-MET mRNA methylation. International Journal of Biological Sciences. 2020;16(14):2595–2611.

[317] Zhou J, Zhang C, Sui X, Cao S, Tang F, Sun S, et al. Histone deacetylase inhibitor chidamide induces growth inhibition and apoptosis in NK/T lymphoma cells through ATM-Chk2-p53-p21 signalling pathway. Invest New Drugs. 2018;36(4):571–580.

[318] Zhao L, Lv C, Sun L, Li Q, Wang Y, Wu M, et al. Histone deacetylase inhibitor chidamide regulates the Wnt/β-catenin pathway by MYCN/DKK3 in B-ALL. Invest New Drugs. 2021;39(4):961–970.

[319] Zhou H, Han L, Wang H, Wei J, Guo Z, Li Z. Chidamide Inhibits Glioma Cells by Increasing Oxidative Stress via the miRNA-338-5p Regulation of Hedgehog Signaling. Oxid Med Cell Long. 2020;2020:7126976.

[320] Wang H, Liu Y-C, Zhu C-Y, Yan F, Wang M-Z, Chen X-S, et al. Chidamide increases the sensitivity of refractory or relapsed acute myeloid leukemia cells to anthracyclines via regulation of the HDAC3 -AKT-P21-CDK2 signaling pathway. Journal of Experimental & Clinical Cancer Research : CR. 2020;39(1):278.

[321] Yen K, Travins J, Wang F, David MD, Artin E, Straley K, et al. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations. Cancer Discov. 2017;7(5):478–493.

[322] Brach D, Johnston-Blackwell D, Drew A, Lingaraj T, Motwani V, Warholic NM, et al. EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL. Mol Cancer Ther. 2017;16(11):2586–2597.

[323] Ishak Gabra MB, Yang Y, Li H, Senapati P, Hanse EA, Lowman XH, et al. Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth. Nat Commun. 2020;11(1):3326.

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