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From splicing noise to therapeutic signaling: RCAN1–4 as a neoepitope in glioblastoma

Cellular & Molecular Immunology volume 23, pages 344–346 (2026)Cite this article

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The Original Article was published on 23 December 2025

Xiong et al. reported a new finding: alternative splicing of RCAN1 (regulator of calcineurin 1, also known as Down syndrome critical region 1), driven by the transcription factor C/EBPβ, produces a glioblastoma-specific isoform (RCAN1-4) that yields an HLA-A24-restricted junctional epitope uniquely recognized by cytotoxic T cells. This discovery links transcriptional reprogramming to antigen generation and establishes RCAN1-4 as a potent immunotherapeutic target in the highly aggressive mesenchymal subtype of glioblastoma (GBM) [1]. By integrating multiomics, immunopeptidomics, and functional TCR-T-cell assays, researchers have demonstrated that tumor-specific splicing junctions can supply functional neoantigens in low-mutation cancers such as GBM. These results not only broaden the repertoire of targetable antigens but also offer a generalizable framework for mining disease-defining splice variants across malignancies.

GBM remains one of the most lethal solid tumors and is resistant to both conventional and immune-based therapies. Its therapeutic ability stems from profound intratumoral heterogeneity, an immunosuppressive milieu, and a paucity of consistent tumor-specific antigens [2]. While neoantigen-directed vaccines and CAR-T-cell therapies have succeeded in selecting cancers, GBM’s low TMB sharply limits such options. However, tumor cells frequently exhibit widespread isoform switching and alternative RNA splicing, generating junctional peptides that are absent in normal tissues [3]. These splicing-derived epitopes could serve as de novo immunogenic targets if properly presented by MHC class I molecules.

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References

  1. Xiong ZKQ, Chagantipati B, Stepniak A, Jaswal AP, Sneiderman CT, et al. C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma. Cell Mol Immunol. 2026;23:94–113.

  2. Singh S, Dey D, Barik D, Mohapatra I, Kim S, Sharma M, et al. Glioblastoma at the crossroads: current understanding and future therapeutic horizons. Signal Transduct Target Ther. 2025;10:213.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Peng Q, Zhou Y, Oyang L, Wu N, Tang Y, Su M, et al. Impacts and mechanisms of alternative mRNA splicing in cancer metabolism, immune response, and therapeutics. Mol Ther. 2022;30:1018–35.

    Article  CAS  PubMed  Google Scholar 

  4. Lee SK, Ahnn J. Regulator of Calcineurin (RCAN): beyond down syndrome critical region. Mol Cells. 2020;43:671–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kahles A, Lehmann KV, Toussaint NC, Hüser M, Stark SG, Sachsenberg T, et al. Comprehensive analysis of alternative splicing across tumors from 8705 patients. Cancer Cell. 2018;34:211–24.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Xie N, Shen G, Gao W, Huang Z, Huang C, Fu L. Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther. 2023;8:9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baulu E, Gardet C, Chuvin N, Depil S. TCR-engineered T-cell therapy in solid tumors: State of the art and perspectives. Sci Adv. 2023;9:eadf3700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang YC, Zhu Y, Sun SJ, Zhao CJ, Bai Y, Wang J, et al. ROS regulation in gliomas: implications for treatment strategies. Front Immunol. 2023;14:1259797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jo Y, Shim JA, Jeong JW, Kim H, Lee SM, Jeong J, et al. Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8(+) T and CAR-T cells. Mol Ther. 2024;32:3879–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2023R1A2C2002435).

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  1. These authors contributed equally: Yuna Jo, So Min Lee.

Authors and Affiliations

  1. Department of Anatomy, Pusan National University School of Medicine, Yangsan, Republic of Korea

    Yuna Jo, So Min Lee & Changwan Hong

  2. Department of Convergence Medical Science, Pusan National University School of Medicine, Yangsan, Republic of Korea

    Yuna Jo, So Min Lee & Changwan Hong

  3. PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan, Republic of Korea

    So Min Lee & Changwan Hong

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  1. Yuna Jo
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Correspondence to Changwan Hong.

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Jo, Y., Lee, S.M. & Hong, C. From splicing noise to therapeutic signaling: RCAN1–4 as a neoepitope in glioblastoma. Cell Mol Immunol 23, 344–346 (2026). https://doi.org/10.1038/s41423-025-01372-w

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