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Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements
Open accessAbstract
Cryptic promoters within transposable elements (TEs) can be transcriptionally reactivated in tumors to create new TE-chimeric transcripts, which can produce immunogenic antigens. We performed a comprehensive screen for these TE exaptation events in 33 TCGA tumor types, 30 GTEx adult tissues and 675 cancer cell lines, and identified 1,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Whole-lysate and HLA-pulldown mass spectrometry data confirmed that TS-TEAs are presented on the surface of cancer cells. In addition, we highlight tumor-specific membrane proteins transcribed from TE promoters that constitute aberrant epitopes on the extracellular surface of cancer cells. Altogether, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that could potentially be therapeutically exploited and targeted.
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“Intriguingly, a prior study uncovered the presence of tumor-specific antigens originating from certain repetitive sequences in various cancers, potentially eliciting immune responses25.”
From Multi-omics analysis identifies glioblastoma dependency on H3K9me3 methyltransferase activity (2025) · cites this paper as [25]
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Combination Therapy Approaches to Enhance the Efficacy of ERV-Targeting Vaccines in Cancer
Gracia-Hernandez, M., Maldonado, M. D. M., Schlom, J., & Hamilton, D. H. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-1192 · Cited by 6
“ERV-derived immunogenic epitopes can be derived via canonical ERV ORFs, chimeric endogenous retroelement–exon tumor antigens (69), or noncanonical splicing junctions between exons and transposable elements (70).”
Exploring transposable elements: new horizons in cancer diagnostics and therapeutics
Chaaban, A., Sleem, R., Santina, J., Rima, M., & Ibrahim, J.-N. (2025) · Mobile DNA · doi:10.1186/s13100-025-00366-9 · Cited by 9
“For instance, although still in the research phase, vaccine designs targeting TE-derived antigens have been proposed [91, 93].”
InfluentialTransposable elements drive species-specific and tissue-specific transcriptomes in human development
Zhang, Y., She, J., Hu, X., Jin, Y., Zhao, J., Hou, S., Tao, C., Du, M., & Yang, E. (2025) · Genome biology · doi:10.1186/s13059-025-03855-5 · Cited by 7
“TE-initiated transcripts have recently been identified using transcript assembly from short-read RNA-seq data [22, 24].”
Transposable element DNA and RNA: Drivers of gene expression, evolution, and disease
Ho, J., Douse, C. H., & Marazzi, I. (2026) · Cell · doi:10.1016/j.cell.2026.05.003 · Cited by 8
Kazachenka, A., Loong, J. H. C., Attig, J., Young, G. R., Ganguli, P., Devonshire, G., Grehan, N., Fitzgerald, R. C., Edwards, P. A., Grehan, N., et al. (2023) · NAR Cancer · doi:10.1093/narcan/zcad040 · Cited by 6
Long-range alternative splicing contributes to neoantigen specificity in glioblastoma
Ji, M., Yu, Q., Yang, X., Yu, X., Wang, J., Xiao, C., An, N. A., Han, C., Li, C., & Ding, W. (2024) · Briefings in Bioinformatics · doi:10.1093/bib/bbae503 · Cited by 6
Meng, X., Nie, Z., Wang, Q., Hu, Y., Deng, Y., Ai, N., Huang, Z., Li, Y., Yuan, Y., Xiao, J., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1235 · Cited by 5
“Notably, widespread activation of TE-derived promoters can generate chimeric transcripts that fuse TE sequences with downstream genes, potentially encoding TE-gene fusion proteins or truncated TE-encoded polypeptides [ 12 –14 ].”
InfluentialKarttunen, K., Patel, D., & Sahu, B. (2024) · BioEssays · doi:10.1002/bies.202400059 · Cited by 5
“[29] Chimeric TE-transcripts also encode immunogenic antigens that are presented on the surface of cancer cells, [67] presenting a promising opportunity to exploit these neoantigens and TE-produced double-stranded RNA (dsRNA) in cancer immunotherapies (reviewed recently by Reid Cahn et al. [68] and…”
Activating the dark genome to illuminate cancer vaccine targets
Kwok, D. W., Okada, H., & Costello, J. (2024) · Nature Genetics · doi:10.1038/s41588-024-01850-3 · Cited by 5
A pan-cancer atlas of therapeutic T cell targetsPreprint
Li, G., Guzmán-Bringas, O. U., Sharma, A., Dellacherie, M. O., Sekhri, P., Yamin, R., Stepec, D., Burq, M., Clotea, I., Tardio, E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.22.634237 · Cited by 6
Lee, S., Ho, Y. Y., Hao, S., Ouyang, Y., Liew, U. L., Goyal, A., Li, S., Barbour, J. A., He, M., Huang, Y., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108568 · Cited by 4
STING agonist-primed supramolecular oncolytic hydrogel vaccine for tuning tumors against themselves
Guo, M., Xie, S., Jiang, C., Tang, M., Zhang, W., Xiong, L., Shang, Q., An, X., & Wang, F. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115032 · Cited by 5
Immunologic specificity in glioblastoma: Antigen discovery and translational implications
Hill, C. M., Wang, A. Z., Hsueh, B., Ramirez, R., Sherpa, N. D., Costa, M. A., Williams, O., Mao, L., & Dunn, G. P. (2025) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdaf028 · Cited by 5
“252 While TE-derived antigens have been classified as tumor-specific, 93,253 the study indicated that many TEs are expressed at low levels in normal tissues.”
Cancer Immunotherapy: How to Exploit Transposable Elements?
Lanciano, S., & Cristofari, G. (2023) · Clinical Chemistry · doi:10.1093/clinchem/hvad091 · Cited by 4
Pan-cancer analysis reveals multifaceted roles of retrotransposon-fusion RNAsPreprint
Lee, B., Park, J., Voshall, A., Maury, E. A., Kang, Y., Kim, Y. J., Lee, J.-Y., Shim, H.-R., Kim, H.-J., Lee, J. W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.16.562422 · Cited by 6
“…of TE-derived peptides, several studies including our previous work suggested that reactivated transposons trigger innate immune responses 17,18,20,42 and might play a more complex, long-term immune-modulatory role in primary tumors leading to the observation of anti-correlation between cancer…”
BackgroundCheng, C. C. Y., Cheung, M. F., Lee, A. Y., Wu, Q., Chow, S. H.-C., Ang, J. Y. J., Riquelme Medina, I., Lo, G., Wu, H., Yang, W., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-09154-w · Cited by 3
“Forexample,globalDNAhypo-methylationcanactivatelong-terminalrepeat(LTR)retrotransposons, includingendogenousretroviruses(ERVs),whichcanfunctionasalter-nativepromotersforoncogenes 30,31 .”
Bright side of the dark genome: antigens for next-gen cancer vaccines
Wang, X., & Fox, B. A. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-014075 · Cited by 6
“167 DPV-001 is also being combined with ICB for the treatment of metastatic/recurrent HNSCC with a reported tripling of responses and increased PFS and OS in a cohort of 18 patients.”
Decoding immunotherapy response through computational modeling
Li, B., Luo, R., Huang, K., Liu, J., Zhao, W., & Zhou, X. (2026) · Nature Communications · doi:10.1038/s41467-026-71364-5 · Cited by 4
Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA
Tanu, T., Cox, A. M., Karlow, J. A., Sharma, P., Sun, K., He, X., Babu, S., Roelofs, M. K., Jeon, E., Chen, J., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117526 · Cited by 5
“15 Transposable elements are upregulated in multiple cancer types, with the ERV class of retroelements being most affected.”
Grundy, E. E., Shaw, L. C., Wang, L., Lee, A. V., Argueta, J. C., Powell, D. J., Ostrowski, M., Jones, R. B., Cruz, C. C., Gordish‐Dressman, H., et al. (2024) · Mobile DNA · doi:10.1186/s13100-024-00333-w · Cited by 3
“Beyond targeting whole TEs as tumor associated antigens, a more effective approach may be to target chimeric TE-derived transcripts, which derive from cryptic promoters within TEs [70].”
BackgroundResultZhu, S., Chen, C., Wang, M., Liu, Y., Li, B., Qi, X., Song, M., Liu, X., Feng, J., & Liu, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-83022-1 · Cited by 3
Xu, J., Liu, J., Wang, Y., Peng, L., Wang, L., Ji, L., Yang, Y., You, B., Huang, Y., Fang, S., et al. (2025) · Translational Oncology · doi:10.1016/j.tranon.2025.102369 · Cited by 3
“Their activity is tightly regulated by epigenetic modifications, primarily DNA methylation, which repress transcription [16 – 18].”
Xu, Y., Huang, Z., Zhang, Y., Gong, M., Wang, Z., Guo, P., Zhang, F., Yang, J., Liang, G., Dong, L., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70645-3 · Cited by 3
Choudalakis, M., Bashtrykov, P., & Jeltsch, A. (2024) · Mobile DNA · doi:10.1186/s13100-024-00315-y · Cited by 3
DNA virus infections shape transposable elements activity in vitro and in vivoPreprint
Tan, J., Franke, V., Neugebauer, E., Pennisi, S., Schaechtle, M. A., Lagisquet, J., Kuderna, A. K., Wälter, S., Welker, I., Ensser, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.18.589901 · Cited by 3
RAmbler resolves complex repeats in human Chromosomes 8, 19, and XPreprint
Chakravarty, S., Logsdon, G. A., & Lonardi, S. (2025) · Genome Research · doi:10.1101/gr.279308.124 · Cited by 3
Genomics guiding personalized first-line immunotherapy response in lung and bladder tumors
Iglesias, J. B., Gallardo‐Gómez, M., Oitabén, A., Lázaro-Quintela, M., León‐Mateos, L., Alves, J. M., Pino-González, M., Juaneda‐Magdalena, L., García-Benito, C., Abdulkader, I., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06323-7 · Cited by 2
Exploiting TCR Repertoire Analysis to Select Therapeutic TCRs for Cancer Immunotherapy
Demaël, U. M., Rirkkrai, T., Okuş, F. Z., Tiffeau-Mayer, A., & Stauss, H. J. (2025) · Cells · doi:10.3390/cells14151223 · Cited by 2
“…literature has explored contributions from the “dark proteome”, including peptides arising from endogenous retroviruses and trans-posable elements [13], aberrant splice variants [14], frameshift mutations [14], circular RNAs [15], and microbial sources [16,17], all of which are processed…”
Molecular effects of transposable element sequences in mammalian cells
Wen, M., & Welch, J. D. (2025) · Genome biology · doi:10.1186/s13059-025-03883-1 · Cited by 2
“Although these mechanisms may contribute to disease in some contexts [13, 15, 17, 100], in other contexts, TEs may serve helpful roles [48, 56].”
Qiao, N., Chen, J., Liu, Y., Chen, Z. J., & Chen, S. J. (2026) · MedScience · doi:10.1007/s11684-026-1210-6 · Cited by 3
Harnessing transposable elements for cancer therapy
Liu, Y., & Han, L. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.05.005 · Cited by 2
Spermine Synthase : A Potential Prognostic Marker for Lower-Grade Gliomas
Liu, C., Li, H., Hu, X., Yan, M., Fu, Z., Zhang, H., Wang, Y., & Du, N. (2024) · Journal of Korean Neurosurgical Society · doi:10.3340/jkns.2024.0080 · Cited by 2
“Before data collection, written informed consent was acquired per the provided guidelines since the TCGA and GTEx databases are publicly accessible 45,48) .”
Method
Metadata
- Authors
- Shah, N. M., Jang, H. J., Liang, Y., Maeng, J. H., Tzeng, S.-C., Wu, A., Basri, N. L., Qu, X., Fan, C., Li, A., Katz, B., Li, D., Xing, X., Evans, B. S., & Wang, T.
- Affiliations
- Washington University in St. Louis (US)
- Van Andel Institute (US)
- Donald Danforth Plant Science Center (US)
- Corresponding author
- Wang, Ting
- ORCID
- Venue
- Nature Genetics
- Published
- 2023-03-27
- Volume
- 55
- Issue
- 4
- Pages
- 631-639
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC13152471
- OpenAlex
- W4360999762
- Cited by
- 175
- References
- 70
- Citations by year
- 2026: 40 · 2025: 61 · 2024: 46 · 2023: 27
- FWCI
- 22.95
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Human Genome Research Institute (R01HG007175, U01HG009391)
- National Institute of General Medical Sciences (T32GM007067)
- National Institute of Environmental Health Sciences (U24ES026699)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- transposable elements, cryptic promoter, tumor-specific antigens, cancer immunotherapy, membrane proteins, pan-cancer analysis, cancer cell lines
- MeSH terms
- Adult, Antigens, Neoplasm, Cell Line, DNA Transposable Elements, Humans, Neoplasms, Promoter Regions, Genetic
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