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

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 Elía, Fiona Megan Tilghman, Hanan Sakeer, Marco Antonio Mendoza-Parra, Angelika B. Riemer (), Reuven Agami () and Fabricio Loayza-Puch ()
Additional contact information
Alexander Kowar: German Cancer Research Center (DKFZ)
Jonas P. Becker: German Cancer Research Center (DKFZ)
Rossella Pizzo: German Cancer Research Center (DKFZ)
Zhiwei Tang: German Cancer Research Center (DKFZ)
Julien Champagne: The Netherlands Cancer Institute
Kathrin Wellach: University of Heidelberg
Kiana Samimi: University of 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)
Reuven Agami: The Netherlands Cancer Institute
Fabricio Loayza-Puch: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63405-2

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