Endogenous Retroviruses: Mechanisms of Action in Embryonic Development, Aging, and Cancer, and Novel Strategies for Targeted Therapy

Yifei Zhang(Zhejiang University)

Abstract

This article reviews the mechanisms of action and research progress of endogenous retroviruses (ERVs) in embryonic development, aging, cancer induction, and targeted therapy. ERVs exhibit stage-specific expression during embryonic development and influence cell differentiation and tissue formation by regulating key genes. During aging, ERV expression is upregulated, which may promote aging by activating immune pathways and inducing the senescence-associated secretory phenotype (SASP). ERVs play a dual role in cancer development. Therapeutic approaches targeting ERVs mainly focus on epigenetic drugs, antiretroviral drugs, and monoclonal antibodies, providing new insights for the treatment of cancer and age-related diseases. This review aims to provide researchers with a comprehensive understanding of the physiological and pathological functions of ERVs and explore their potential as novel biomarkers and intervention targets.

Keywords

Endogenous retroviruses; Tumors; Cancer; Aging-related diseases; Development; Human health

References

STOYE J P. Studies of endogenous retroviruses reveal a continuing evolutionary saga [J]. Nature reviews microbiology, 2012, 10(6): 395-406.

SUBRAMANIAN R P, WILDSCHUTTE J H, RUSSO C, et al. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses [J]. Retrovirology, 2011, 8: 90.

LAWSON H A, LIANG Y, WANG T. Transposable elements in mammalian chromatin organization [J]. Nature reviews genetics, 2023, 24(10): 712-723.

HUGHES J F, COFFIN J M. Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolution [J]. Nature genetics, 2001, 29(4): 487-489.

GÖKE J, LU X, CHAN Y S, et al. Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells [J]. Cell stem cell, 2015, 16(2): 135-141.

LICASTRO F, PORCELLINI E. Activation of endogenous retrovirus, brain infections and environmental insults in neurodegeneration and Alzheimer’s disease [J]. International journal of molecular sciences, 2021, 22(14): 7263.

Li T T. Study on RNA Editing and ERV Function during Early Embryonic Development of Mammals Based on Multi-Omics [D]. Shaanxi: Northwest A&F University, 2020.

Mortelmans Kristien, Wang-Johanning Feng, Johanning Gary L. The role of human endogenous retroviruses in brain development and function[J]. APMIS,2016,124(1-2):105-115.

BEYER U, MOLL-ROCEK J, MOLL U M, et al. Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes[J]. Proceedings of the National Academy of Sciences of the United States of America,2011,108(9):3624-3629. DOI:10.1073/pnas.1016201108.

DURRUTHY-DURRUTHY J, SEBASTIANO V, WOSSIDLO M, et al. The primate-specific noncoding RNA HPAT5 regulates pluripotency during human preimplantation development and nuclear reprogramming[J]. Nature Genetics,2016,48(1):44-52. DOI:10.1038/ng.3449.

Wang J C, Singh M, Sun C B, et al. Isolation and cultivation of naive-like human pluripotent stem cells based on HERVH expression[J]. Nature Protocols,2016,11(2):327-346. DOI:10.1038/nprot.2016.016.

Li W J. Functional Study of Endogenous Retroviral Sequence ERV1 in Regulating Early Embryonic Development of Goats [D]. Shaanxi: Northwest A&F University, 2021.

Nataf Serge, Uriagereka Juan, Benitez-Burraco Antonio. The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the ER4l primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition[J]. Front Genet,2019,10:321.

MI S, LEE X, LI X, et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis [J]. Nature, 2000, 403(6771): 785-789.

CHUONG E B, RUMI M A, SOARES M J, et al. Endogenous retroviruses function as species-specific enhancer elements in the placenta [J]. Nature genetics, 2013, 45(3): 325-329.

DUNN-FLETCHER C E, MUGLIA L M, PAVLICEV M, et al. Anthropoid primate-specific retroviral element THE1B controls expression of CRH in placenta and alters gestation length [J]. PLoS biology, 2018, 16(9): e2006337.

FROST J M, AMANTE S M, OKAE H, et al. Regulation of human trophoblast gene expression by endogenous retroviruses [J]. Nature structural & molecular biology, 2023, 30(4): 527-538.

DU C, JIANG J, LI Y, et al. Regulation of endogenous retrovirus-derived regulatory elements by GATA2/3 and MSX2 in human trophoblast stem cells [J]. Genome research, 2023, 33(2): 197-207.

ALMEIDA M V, VERNAZ G, PUTMAN A L K, et al. Taming transposable elements in vertebrates: from epigenetic silencing to domestication [J]. Trends in genetics, 2022, 38(6): 529-553.

GAUTAM P, YU T, LOH Y H. Regulation of ERVs in pluripotent stem cells and reprogramming [J]. Current opinion in genetics & development, 2017, 46: 194-201.

YANG B X, EL FARRAN C A, GUO H C, et al. Systematic identification of factors for provirus silencing in embryonic stem cells [J]. Cell, 2015, 163(1): 230-245.

XU W, LI J, HE C, et al. METTL3 regulates heterochromatin in mouse embryonic stem cells [J]. Nature, 2021, 591(7849): 317-321.

Brady T, Lee Y N, Ronen K, et al. Integration target site selection by a resurrected human endogenous retrovirus[J]. Genes and Development: a Journal Devoted to the Molecular Analysis of Gene Expression in Eukaryotes, Prokaryotes, and Viruses,2009,23(5):633-642.

ROWE H M, KAPOPOULOU A, CORSINOTTI A, et al. TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells[J]. Genome research,2013,23(3):452-461. DOI:10.1101/gr.147678.112.

REBOLLO R, MICELI-ROYER K, ZHANG Y, et al. Epigenetic interplay between mouse endogenous retroviruses and host genes[J]. Genome Biology,2012,13(10):R99.

Talepoor AG, Doroudchi M (2022). Immunosenescence in atherosclerosis: A role for chronic viral infections. Front Immunol, 13:16.

Li X, Li CT, Zhang WY, Wang YA, Qian PX, Huang H (2023). Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther, 8:29.

Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al (2019). Cellular Senescence: Defining a Path Forward. Cell, 179:813-827.

Nilsson AR, Soneji S, Adolfsson S, Bryder D, Pronk CJ (2016). Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias. PLoS One, 11:e0155365.

De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA (2013). Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging (Albany NY), 5:867-883.

Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J, et al (2013). Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell, 12:247-256.

Capone S, Connor KM, Colombo A, Li X, Triche TJ, Ramsingh G (2018). Senescent human hematopoietic progenitors show elevated expression of transposable elements and inflammatory genes. Exp Hematol, 62:33-38.

Zhang H, Li J, Yu Y, et al. Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging. Cell Rep, 2023, 42: 112593.

Yang S, Liu C, Jiang M, et al. A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes. Protein Cell, 2024, 15: 98-120.

Zhang H, Li J, Yu Y, et al. Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging. Cell Rep, 2023, 42: 112593.

Autio A, Nevalainen T, Mishra B H, et al. Effect of aging on the transcriptomic changes associated with the expression of the HERV-K (HML-2) provirus at 1q22. Immun Ageing, 2020, 17: 11.

Nevalainen T, Autio A, Mishra B H, et al. Aging-associated patterns in the expression of human endogenous retroviruses. PLoS ONE, 2018, 13: e0207407.

Balestrieri E, Pica F, Matteucci C, et al. Transcriptional activity of human endogenous retroviruses in human peripheral blood mononuclear cells. Biomed Res Int, 2015, 2015: 1-9.

Capone S, Connor K M, Colombo A, et al. Senescent human hematopoietic progenitors show elevated expression of transposable elements and inflammatory genes. Exp Hematol, 2018, 62: 33-38.e6.

Colombo A R, Elias H K, Ramsingh G. Senescence induction universally activates transposable element expression. Cell Cycle, 2018, 17: 1846–1857.

LIU X, LIU Z, WU Z, et al. Resurrection of endogenous retroviruses during aging reinforces senescence [J]. Cell, 2023, 186(2): 287-304.

ZHANG H, LI J, YU Y, et al. Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging [J]. Cell reports, 2023, 42(6): 112593.

Yu HL, Zhao ZK, Zhu F. The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)[J]. Int J Mol Med, 2013, 32(4): 755-762.

Yu HL, Zhao ZK, Zhu F. The role of human endogenous retroviral long terminal repeat sequences in human cancer (Review)[J]. Int J Mol Med, 2013, 32(4): 755-762.

Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer [J]. Nature, 2007, 448(7153): 595-599.

Chen T, Meng Z, Gan Y, et al. The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem progenitor cells [J]. Leukemia, 2013, 27(7): 1469-1478.

Lemaitre C, Tsang J, Bireau C, et al. A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion [J]. PLoS Pathog, 2017, 13(6): e1006451.

Goke J, Ng HH. CTRL INSERT: retrotransposons and their contribution to regulation and innovation of the transcriptome [J]. EMBO Rep, 2016, 17(8): 1131-1144.

Garcia-Montojo M, Doucet-O’Hare T, Henderson L, et al. Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit Rev Microbiol, 2018, 44: 715–738.

Wiesner T, Lee W, Obenauf A C, et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature, 2015, 526: 453–457.

Lamprecht B, Walter K, Kreher S, et al. Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med, 2010, 16: 571–579.

Karttunen K, Patel D, Xia J, et al. Transposable elements as tissue-specific enhancers in cancers of endodermal lineage. Nat Commun, 2023, 14: 5313.

Deniz Ö, Ahmed M, Todd C D, et al. Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia. Nat Commun, 2020, 11: 3506.

Yu C, Lei X, Chen F, et al. ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription. Nat Commun, 2022, 13: 3501.

Tavakolian S, Goudarzi H, Moridi A, et al. Analysing the HERV-K env, np9, rec and gag expression in cervical tissues. New Microbes New Infects, 2021, 44: 100936.

Chen T, Meng Z, Gan Y, et al. The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells. Leukemia, 2013, 27: 1469–1478.

Mi S, Lee X, Li X P, et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature, 2000, 403: 785–789.

Chiappinelli K B, Strissel P L, Desrichard A, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell, 2015, 162: 974–986.

Stone M L, Chiappinelli K B, Li H, et al. Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc Natl Acad Sci USA, 2017, 114: E10981–E10990.

de Cubas A A, Dunker W, Zaninovich A, et al. DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer. JCI Insight, 2020, 5: e137569.

Goel S, Decristo M J, Watt A C, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature, 2017, 548: 471–475.

Topper M J, Vaz M, Chiappinelli K B, et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell, 2017, 171: 1284–1300.e21.

Takahashi Y, Harashima N, Kajigaya S, et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest, 2008, 118: 1099–1109.

Cherkasova E, Scrivani C, Doh S, et al. Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer. Cancer Res, 2016, 76: 2177–2185.

Smith C C, Beckermann K E, Bortone D S, et al. Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J Clin Invest, 2018, 128: 4804–4820.

Bonaventura P, Alcazer V, Mutez V, et al. Identification of shared tumor epitopes from endogenous retroviruses inducing high-avidity cytotoxic T cells for cancer immunotherapy. Sci Adv, 2022, 8: eabj3671.

Attig J, Young G R, Hosie L, et al. LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly. Genome Res, 2019, 29: 1578–1590.

Bonté P E, Arribas Y A, Merlotti A, et al. Single-cell RNA-seq-based proteogenomics identifies glioblastoma-specific transposable elements encoding HLA-I-presented peptides. Cell Rep, 2022, 39: 110916.

Brocks D, Schmidt C R, Daskalakis M, et al. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat Genet, 2017, 49: 1052–1060.

Goyal A, Bauer J, Hey J, et al. DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts. Nat Commun, 2023, 14: 6731.

Krishnamurthy J, Rabinovich B A, Mi T, et al. Genetic engineering of T cells to target HERV-K, an ancient retrovirus on melanoma. Clin Cancer Res, 2015, 21: 3241–3251.

Capone S, Connor K M, Colombo A, et al. Senescent human hematopoietic progenitors show elevated expression of transposable elements and inflammatory genes. Exp Hematol, 2018, 62: 33–38.e6.

Capone S, Connor K M, Colombo A, et al Senescent human hematopoietic progenitors show elevated expression of transposable elements and inflammatory genes. Exp Hematol, 2018, 62: 33–38.e6.

Locke WJ, Guanzon D, Ma CK, Liew YJ, Duesing KR, Fung KYC, et al (2019). DNA Methylation Cancer Biomarkers: Translation to the Clinic. Front Genet, 10:22.

Ku Y, Park JH, Cho R, Lee Y, Park HM, Kim M, et al (2021). Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs. Proc Natl Acad Sci U S A, 118:12.

Kogan AA, Topper MJ, Dellomo AJ, Stojanovic L, McLaughlin LJ, Creed TM, et al (2022). Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia. Proc Natl Acad Sci U S A, 119:12.

Roulois D, Yau HL, Singhania R, Wang YD, Danesh A, Shen SY, et al (2015). DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell, 162:961-973.

Chiappinelli KB, Strissel PL, Desrichard A, Li HL, Henke C, Akman B, et al (2015). Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell, 162:974-986.

Weber J, Salgaller M, Samid D, Johnson B, Herlyn M, Lassam N, et al (1994). Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2'deoxycytidine. Cancer Res, 54:1766-1771.

Qiu XN, Hother C, Ralfkiaer UM, Sogaard A, Lu QJ, Workman CT, et al (2010). Equitoxic Doses of 5Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome. PLoS One, 5:10.

Takahashi Y, Harashima N, Kajigaya S, Yokoyama H, Cherkasova E, McCoy JP, et al (2008). Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERVE antigen by T cells. J Clin Invest, 118:1099-1109.

Bonaventura P, Alcazer V, Mutez V, Tonon L, Martin J, Chuvin N, et al (2022). Identification of shared tumor epitopes from endogenous retroviruses inducing highavidity cytotoxic T cells for cancer immunotherapy. Sci Adv, 8:15.

Walton TJ, Li G, Seth R, McArdle SE, Bishop MC, Rees RC (2008). DNA demethylation and histone deacetylation inhibition co-operate to re-express estrogen receptor beta and induce apoptosis in prostate cancer cell-lines. Prostate, 68:210-222.

Goyal A, Bauer J, Hey J, Papageorgiou DN, Stepanova E, Daskalakis M, et al (2023). DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts. Nat Commun, 14:6731.

Mehdipour P, Marhon SA, Ettayebi I, Chakravarthy A, Hosseini A, Wang YD, et al (2020). Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency. Nature, 588:169-173.

Fang Y, Zhang MC, He Y, Li C, Fang H, Xu PP, et al (2023). Human endogenous retroviruses as epigenetic therapeutic targets in TP53-mutated diffuse large B-cell lymphoma. Signal Transduct Target Ther, 8:13.

Zhang MC, Fang Y, Xu PP, Dong L, Shen R, Huang YH, et al (2021). Clinical efficacy and tumour microenvironment influence of decitabine plus R-CHOP in patients with newly diagnosed diffuse large B-Cell lymphoma: Phase 1/2 and biomarker study. Clin Transl Med, 11:e584.

Li WX, Pandya D, Pasternack N, Garcia-Montojo M, Henderson L, Kozak CA, et al (2022). Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis. Neurotherapeutics, 19:1085-1101.

Contreras-Galindo R, Dube D, Fujinaga K, Kaplan MH, Markovitz DM (2017). Susceptibility of Human Endogenous Retrovirus Type K to Reverse Transcriptase Inhibitors. J Virol, 91:18.

Towler EM, Gulnik SV, Bhat TN, Xie D, Gustschina E, Sumpter TR, et al (1998). Functional characterization of the protease of human endogenous retrovirus, K10: Can it complement HIV-1 protease? Biochemistry, 37:1713717144.

Tyagi R, Li WX, Parades D, Bianchet MA, Nath A (2017). Inhibition of human endogenous retrovirus-K by antiretroviral drugs. Retrovirology, 14:13.

Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, Van Eijk RPA, et al (2019). Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial. Amyotroph Lateral Scler Frontotemporal Degener, 20:595604.

Morandi E, Tanasescu R, Tarlinton RE, Constantin-Teodosiu D, Gran B (2019). Do Antiretroviral Drugs Protect From Multiple Sclerosis by Inhibiting Expression of MS-Associated Retrovirus? Front Immunol, 9:11.

Gold J, Marta M, Meier UC, Christensen T, Miller D, Altmann D, et al (2018). A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study. Mult Scler Relat Disord, 24:123128.

Mangiacasale R, Pittoggi C, Sciamanna I, Careddu A, Mattei E, Lorenzini R, et al (2003). Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation. Oncogene, 22:2750-2761.

Carlini F, Ridolfi B, Molinari A, Parisi C, Bozzuto G, Toccacieli L, et al (2010). The Reverse Transcription Inhibitor Abacavir Shows Anticancer Activity in Prostate Cancer Cell Lines. PLoS One, 5:13.

]Maze EA, Agit B, Reeves S, Hilton DA, Parkinson DB, Laraba L, et al (2022). Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma. Cancer Res, 82:235-247.

Curtin F, Champion B, Davoren P, Duke S, Ekinci EI, Gilfillan C, et al (2020). A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes. Diabetes Obes Metab, 22:1111-1121.

Curtin F, Bernard C, Levet S, Perron H, Porchet H, Médina J, et al (2018). A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody. Diabetes Obes Metab, 20:2075-2084.

Hartung HP, Derfuss T, Cree BA, Sormani MP, Selmaj K, Stutters J, et al (2022). Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study. Mult Scler, 28:429-440.

Li XH, Wu XL, Li WS, Yan QJ, Zhou P, Xia YR, et al (2023). HERV-W ENV Induces Innate Immune Activation and Neuronal Apoptosis via linc01930/cGAS Axis in Recent-Onset Schizophrenia. Int J Mol Sci, 24:26.

Yan Q, Wu X, Zhou P, Zhou Y, Li X, Liu Z, et al (2022). HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk. Viruses, 14.

Steiner JP, Bachani M, Malik N, DeMarino C, Li WX, Sampson K, et al (2022). Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic. Ann Neurol, 92:545-561.

Wang-Johanning F, Rycaj K, Plummer JB, Li M, Yin BN, Frerich K, et al (2012). Immunotherapeutic Potential of Anti-Human Endogenous Retrovirus-K Envelope Protein Antibodies in Targeting Breast Tumors. J Natl Cancer Inst, 104:189-210.

Barisic S, Brahmbhatt EM, Cherkasova E, Nadal R, Savani U, Pierre S, et al (2023). T cell receptor-engineered T cells targeting a human endogenous retrovirus in kidney cancer.J Clin Oncol, 41:1.

Tokuyama M, Gunn BM, Venkataraman A, Kong Y, Kang I, Rakib T, et al (2021). Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus. J Exp Med, 218:20.

Zhang Yifei, born in September 2004, is a female of Han ethnicity from Hengyang, Hunan Province. She is currently an undergraduate student and is engaged in research related to the mechanism of cancer occurrence and tumor target screening.

DOI: http://dx.doi.org/10.26549/jor.v7i1.32017