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Updated: Sep 10, 2025

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

Alexander Kowar1,2, Jonas P Becker3,4, Rossella Del Pizzo1,2

  • 1Translational Control and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Nature Communications
|August 27, 2025
PubMed

Insights

Cancer cells exploit mitosis by enhancing translation of specific gene regions, creating targets for immune cells. Targeting these upstream open reading frames (uORFs) with mitotic inhibitors can improve cancer immunotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Mitosis is a crucial cell cycle stage targeted in cancer therapy.
  • Drug resistance and suppressed translation during mitosis pose challenges.
  • Non-canonical translation persists in cancer cells during mitosis.

Purpose of the Study:

  • To investigate ribosome redistribution and translation regulation during mitosis in cancer cells.
  • To explore the impact of mitotic translation on cancer cell surface antigen presentation.
  • To assess the therapeutic potential of targeting mitotic translation for cancer immunotherapy.

Main Methods:

  • Analysis of ribosome distribution in mitotic cancer cells.
  • Identification and quantification of translated upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs).
  • Assessment of human leukocyte antigen (HLA) presentation of neoantigens and T cell-mediated cancer cell killing assays.

Main Results:

  • Mitotic cancer cells exhibit ribosome redistribution towards 5' untranslated regions (5' UTRs) and coding sequences (CDS).
  • This redistribution enhances the translation of thousands of uORFs and uoORFs.
  • Mitotic inhibitor treatment increases the presentation of non-canonical peptides derived from uORFs/uoORFs on cancer cells, stimulating T cell responses.

Conclusions:

  • Targeting uORF/uoORF translation during mitosis offers a novel strategy to enhance cancer immunotherapy.
  • Mitotic inhibitors combined with therapies targeting uORF/uoORF-derived epitopes can improve immune recognition and tumor elimination.
  • This approach holds promise for overcoming drug resistance and improving cancer treatment outcomes.

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