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Upstream open reading frame translation enhances immunogenic peptide presentation in mitotically arrested cancer cells

Author

Listed:
  • Alexander Kowar

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • Jonas P. Becker

    (German Cancer Research Center (DKFZ)
    a partnership between DKFZ and University Hospital)

  • Rossella Pizzo

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • Zhiwei Tang

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • Julien Champagne

    (The Netherlands Cancer Institute)

  • Kathrin Wellach

    (University of Heidelberg
    German Cancer Research Center (DKFZ)
    partner site Heidelberg)

  • Kiana Samimi

    (University of Heidelberg
    German Cancer Research Center (DKFZ)
    partner site Heidelberg)

  • Ariel Galindo-Albarrán

    (University Paris-Saclay)

  • Pierre-René Körner

    (The Netherlands Cancer Institute)

  • Jasmine Montenegro Navarro

    (The Netherlands Cancer Institute)

  • Andrés Elía

    (German Cancer Research Center (DKFZ))

  • Fiona Megan Tilghman

    (German Cancer Research Center (DKFZ))

  • Hanan Sakeer

    (German Cancer Research Center (DKFZ))

  • Marco Antonio Mendoza-Parra

    (University Paris-Saclay)

  • Angelika B. Riemer

    (German Cancer Research Center (DKFZ)
    partner site Heidelberg)

  • Reuven Agami

    (The Netherlands Cancer Institute)

  • Fabricio Loayza-Puch

    (German Cancer Research Center (DKFZ))

Abstract

Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canonical translation of specific transcripts continues. Here, we show that mitotic cancer cells redistribute ribosomes toward the 5′ untranslated region (5′ UTR) and beginning of the coding sequence (CDS), enhancing translation of thousands of upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs). This mitotic induction of uORF/uoORF enriches human leukocyte antigen (HLA) presentation of non-canonical peptides on the surface of cancer cells after mitotic inhibitor treatment. Functional assays indicate these epitopes provoke cancer-cell killing by T cells. Our findings highlight the therapeutic potential of targeting uORF/uoORF-derived epitopes with mitotic inhibitors to enhance immune recognition and tumor cell elimination.

Suggested Citation

  • Alexander Kowar & Jonas P. Becker & Rossella Pizzo & Zhiwei Tang & Julien Champagne & Kathrin Wellach & Kiana Samimi & Ariel Galindo-Albarrán & Pierre-René Körner & Jasmine Montenegro Navarro & Andrés, 2025. "Upstream open reading frame translation enhances immunogenic peptide presentation in mitotically arrested cancer cells," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63405-2
    DOI: 10.1038/s41467-025-63405-2
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