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image of Potential of Circular RNAs (circRNAs) Neoantigen Vaccines in Tumor Immunotherapy

Abstract

Circular RNAs (circRNAs) have emerged as promising candidates for neoantigen vaccine development due to their unique structural stability, enhanced translational efficiency, and immunostimulatory properties. Unlike linear RNAs, circRNAs exhibit exonuclease resistance, prolonged antigen expression, and increased activation of innate immune receptors such as RIG-I and MDA5, thereby enhancing anti-tumor immune responses. Preclinical studies have demonstrated that circRNA-based vaccines encoding tumor-specific neoantigens effectively stimulate Antigen-Presenting Cells (APCs), particularly Dendritic Cells (DCs), leading to robust CD8+ Cytotoxic T Lymphocyte (CTL) activation. This results in increased cytokine production, T-cell proliferation, and durable anti-tumor immunity. Compared to conventional neoantigen vaccine platforms, circRNA vaccines offer distinct advantages, including higher immunogenicity, improved cytosolic delivery, and minimal risk of genomic integration. CircRNA vaccines have demonstrated efficacy in preclinical tumor models, with studies highlighting their ability to induce long-term memory T-cell responses and enhance the efficacy of immune checkpoint blockade therapies. However, challenges remain in optimizing circRNA delivery, mitigating unintended immune activation, and scaling up manufacturing processes. The translational potential of circRNA vaccines in tumor immunotherapy is significant, offering a novel and scalable approach to personalized cancer treatment. Further research and clinical validation are needed to optimize their design, improve manufacturing efficiency, and assess their efficacy in human trials. CircRNA vaccines represent a next-generation platform with the potential to revolutionize cancer immunotherapy by harnessing durable and targeted anti-tumor immune responses.

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2025-05-26
2025-09-01
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References

  1. Hussain M.S. Moglad E. Bansal P. Kaur H. Deorari M. almalki W.H. Kazmi I. Alzarea S.I. Singh M. Kukreti N. Exploring the oncogenic and tumor-suppressive roles of Circ-ADAM9 in cancer. Pathol. Res. Pract. 2024 256 155257 10.1016/j.prp.2024.155257 38537524
    [Google Scholar]
  2. Ma Z. Shuai Y. Gao X. Wen X. Ji J. Circular RNAs in the tumour microenvironment. Mol. Cancer 2020 19 1 8 10.1186/s12943‑019‑1113‑0 31937318
    [Google Scholar]
  3. Chen Y.G. Kim M.V. Chen X. Batista P.J. Aoyama S. Wilusz J.E. Iwasaki A. Chang H.Y. Sensing self and foreign circular RNAs by intron identity. Mol. Cell 2017 67 2 228 238.e5 10.1016/j.molcel.2017.05.022 28625551
    [Google Scholar]
  4. Wu J. Chen Z.J. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 2014 32 1 461 488 10.1146/annurev‑immunol‑032713‑120156 24655297
    [Google Scholar]
  5. Hussain M.S. Moglad E. Afzal M. Bansal P. Kaur H. Deorari M. Ali H. Shahwan M. Hassan almalki W. Kazmi I. Alzarea S.I. Singh S.K. Dua K. Gupta G. Circular RNAs in the KRAS pathway: Emerging players in cancer progression. Pathol. Res. Pract. 2024 256 155259 10.1016/j.prp.2024.155259 38503004
    [Google Scholar]
  6. Qu L. Yi Z. Shen Y. Lin L. Chen F. Xu Y. Wu Z. Tang H. Zhang X. Tian F. Wang C. Xiao X. Dong X. Guo L. Lu S. Yang C. Tang C. Yang Y. Yu W. Wang J. Zhou Y. Huang Q. Yisimayi A. Liu S. Huang W. Cao Y. Wang Y. Zhou Z. Peng X. Wang J. Xie X.S. Wei W. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell 2022 185 10 1728 1744.e16 10.1016/j.cell.2022.03.044 35460644
    [Google Scholar]
  7. Tang X. Qi C. Zhou H. Liu Y. Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy. Front. Oncol. 2022 12 972906 10.3389/fonc.2022.972906 35957898
    [Google Scholar]
  8. Chen J. Zhao X. Yuan Y. Jing J.J. The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers. Cancer Cell Int. 2020 20 1 238 10.1186/s12935‑020‑01315‑7 32536826
    [Google Scholar]
  9. Wang F. Cai G. Wang Y. Zhuang Q. Cai Z. Li Y. Gao S. Li F. Zhang C. Zhao B. Liu X. Circular RNA-based neoantigen vaccine for hepatocellular carcinoma immunotherapy. MedComm 2024 5 8 e667 10.1002/mco2.667 39081513
    [Google Scholar]
  10. Amaya L. Grigoryan L. Li Z. Lee A. Wender P.A. Pulendran B. Chang H.Y. Circular RNA vaccine induces potent T cell responses. Proc. Natl. Acad. Sci. USA 2023 120 20 e2302191120 10.1073/pnas.2302191120 37155869
    [Google Scholar]
  11. Acevedo-Whitehouse K. Bruno R. Potential health risks of mRNA-based vaccine therapy: A hypothesis. Med. Hypotheses 2023 171 111015 10.1016/j.mehy.2023.111015 36718314
    [Google Scholar]
  12. Hussain M.S. Moglad E. Afzal M. Sharma S. Gupta G. Sivaprasad G.V. Deorari M. Almalki W.H. Kazmi I. Alzarea S.I. Shahwan M. Pant K. Ali H. Singh S.K. Dua K. Subramaniyan V. Autophagy-associated non-coding RNAs: Unraveling their impact on Parkinson’s disease pathogenesis. CNS Neurosci. Ther. 2024 30 5 e14763 10.1111/cns.14763 38790149
    [Google Scholar]
  13. Huang D. Zhu X. Ye S. Zhang J. Liao J. Zhang N. Zeng X. Wang J. Yang B. Zhang Y. Lao L. Chen J. Xin M. Nie Y. Saw P.E. Su S. Song E. Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides. Nature 2024 625 7995 593 602 10.1038/s41586‑023‑06834‑7 38093017
    [Google Scholar]
  14. Gupta A. Rudra A. Reed K. Langer R. Anderson D.G. Advanced technologies for the development of infectious disease vaccines. Nat. Rev. Drug Discov. 2024 23 12 914 938 10.1038/s41573‑024‑01041‑z 39433939
    [Google Scholar]
  15. Hobernik D. Bros M. DNA vaccines: How far from clinical use? Int. J. Mol. Sci. 2018 19 11 3605 10.3390/ijms19113605 30445702
    [Google Scholar]
  16. Zhao X. Zhong Y. Wang X. Shen J. An W. Advances in circular RNA and its applications. Int. J. Med. Sci. 2022 19 6 975 985 10.7150/ijms.71840 35813288
    [Google Scholar]
  17. Hussain M.S. Moglad E. Afzal M. Gupta G. Hassan Almalki W. Kazmi I. Alzarea S.I. Kukreti N. Gupta S. Kumar D. Chellappan D.K. Singh S.K. Dua K. Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives. Pathol. Res. Pract. 2024 258 155303 10.1016/j.prp.2024.155303 38728793
    [Google Scholar]
  18. Liu X Zhang Y Zhou S Dain L Mei L Zhu G. Circular RNA: An emerging frontier in RNA therapeutic targets, RNA therapeutics, and mRNA vaccines. J. Control Release. 2022 348 84 94 10.1016/j.jconrel.2022.05.043
    [Google Scholar]
  19. Shi Y. Zhen X. Zhang Y. Li Y. Koo S. Saiding Q. Kong N. Liu G. Chen W. Tao W. Chemically modified platforms for better RNA therapeutics. Chem. Rev. 2024 124 3 929 1033 10.1021/acs.chemrev.3c00611 38284616
    [Google Scholar]
  20. Rahman M. Dendritic cell-based cancer vaccine production. Metabolomics for Personalized Vaccinology. Elsevier 2024 341 375 10.1016/B978‑0‑443‑15526‑0.00006‑8
    [Google Scholar]
  21. Gupta R. Arora K. Mehrotra Arora N. Kundu P. Significance of VLPs in Vlp-circRNA vaccines: A vaccine candidate or delivery vehicle? RNA Biol. 2024 21 1 917 928 10.1080/15476286.2024.2399307 39240021
    [Google Scholar]
  22. Maqbool M. Hussain M.S. Shaikh N.K. Sultana A. Bisht A.S. Agrawal M. Noncoding RNAs in the COVID-19 Saga: An untold story. Viral Immunol. 2024 37 6 269 286 10.1089/vim.2024.0026 38968365
    [Google Scholar]
  23. Loan Young T. Chang Wang K. James Varley A. Li B. Clinical delivery of circular RNA: Lessons learned from RNA drug development. Adv. Drug Deliv. Rev. 2023 197 114826 10.1016/j.addr.2023.114826 37088404
    [Google Scholar]
  24. Wesselhoeft R.A. Kowalski P.S. Anderson D.G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 2018 9 1 2629 10.1038/s41467‑018‑05096‑6 29980667
    [Google Scholar]
  25. Chen X. Lu Y. Circular RNA: Biosynthesis in vitro. Front. Bioeng. Biotechnol. 2021 9 787881 10.3389/fbioe.2021.787881 34917603
    [Google Scholar]
  26. Zhang Y. Liu X. Shen T. Wang Q. Zhou S. Yang S. Liao S. Su T. Mei L. Zhang B. Huynh K. Xie L. Guo Y. Guo C. Tyc K.M. Qu X. Wang X.Y. Liu J. Zhu G. Small circular RNAs as vaccines for cancer immunotherapy. Nat. Biomed. Eng. 2025 9 2 249 267 10.1038/s41551‑025‑01344‑5 39920212
    [Google Scholar]
  27. Massaro C. Sgueglia G. Frattolillo V. Baglio S.R. Altucci L. Dell’Aversana C. Extracellular vesicle-based nucleic acid delivery: Current advances and future perspectives in cancer therapeutic strategies. Pharmaceutics 2020 12 10 980 10.3390/pharmaceutics12100980 33081417
    [Google Scholar]
  28. Li H. Peng K. Yang K. Ma W. Qi S. Yu X. He J. Lin X. Yu G. Circular RNA cancer vaccines drive immunity in hard-to-treat malignancies. Theranostics 2022 12 14 6422 6436 10.7150/thno.77350 36168634
    [Google Scholar]
  29. Lee K.H. Kim S. Lee S.W. Pros and cons of in vitro methods for circular RNA preparation. Int. J. Mol. Sci. 2022 23 21 13247 10.3390/ijms232113247 36362032
    [Google Scholar]
  30. Petkovic S. Müller S. RNA circularization strategies in vivo and in vitro. Nucleic Acids Res. 2015 43 4 2454 2465 10.1093/nar/gkv045 25662225
    [Google Scholar]
  31. Minh A. Kamen A.A. Critical assessment of purification and analytical technologies for enveloped viral vector and vaccine processing and their current limitations in resolving co-expressed extracellular vesicles. Vaccines 2021 9 8 823 10.3390/vaccines9080823 34451948
    [Google Scholar]
  32. Kang D.D. Li H. Dong Y. Advancements of in vitro transcribed mRNA (IVT mRNA) to enable translation into the clinics. Adv. Drug Deliv. Rev. 2023 199 114961 10.1016/j.addr.2023.114961 37321375
    [Google Scholar]
  33. Qu Y. Liu R. Sun D. Dai Z. Critical considerations of mRNA–LNP technology for CAR-T therapy: Components, payloads and emerging horizons. Mater. Chem. Front. 2024 8 19 3106 3135 10.1039/D4QM00479E
    [Google Scholar]
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