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Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment

Author

Listed:
  • Daniela Aviles-Huerta

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

  • Rossella Del Pizzo

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

  • Alexander Kowar

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

  • Ali Hyder Baig

    (German Cancer Research Center (DKFZ))

  • Giuliana Palazzo

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

  • Ekaterina Stepanova

    (German Cancer Research Center (DKFZ))

  • Cinthia Claudia Amaya Ramirez

    (German Cancer Research Center (DKFZ))

  • Sara D’Agostino

    (German Cancer Research Center (DKFZ))

  • Edoardo Ratto

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

  • Catarina Pechincha

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

  • Nora Siefert

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

  • Helena Engel

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

  • Shangce Du

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

  • Silvia Cadenas-De Miguel

    (KU Leuven)

  • Beiping Miao

    (German Cancer Research Center (DKFZ))

  • Victor M. Cruz-Vilchez

    (German Cancer Research Center (DKFZ))

  • Karin Müller-Decker

    (German Cancer Research Center (DKFZ))

  • Ilaria Elia

    (KU Leuven)

  • Chong Sun

    (German Cancer Research Center (DKFZ))

  • Wilhelm Palm

    (German Cancer Research Center (DKFZ))

  • Fabricio Loayza-Puch

    (German Cancer Research Center (DKFZ))

Abstract

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

Suggested Citation

  • Daniela Aviles-Huerta & Rossella Del Pizzo & Alexander Kowar & Ali Hyder Baig & Giuliana Palazzo & Ekaterina Stepanova & Cinthia Claudia Amaya Ramirez & Sara D’Agostino & Edoardo Ratto & Catarina Pech, 2025. "Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59986-7
    DOI: 10.1038/s41467-025-59986-7
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