Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment
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.
Authors
- Edoardo Ratto (ORCID: https://orcid.org/0000-0002-4104-7556)
- Wilhelm Palm (ORCID: https://orcid.org/0000-0003-0612-770X)
- Karin Müller‐Decker (ORCID: https://orcid.org/0000-0002-0466-845X)
- Stefania D’Agostino (ORCID: https://orcid.org/0000-0001-6938-6851)
- Chong Sun (ORCID: https://orcid.org/0000-0001-9008-2158)
- Catarina Pechincha (ORCID: https://orcid.org/0000-0002-4650-4250)
- Fabricio Loayza‐Puch (ORCID: https://orcid.org/0000-0002-2999-8594)
- Nora Siefert (ORCID: https://orcid.org/0000-0002-1101-2264)
- Rossella Del Pizzo
- Shangce Du (ORCID: https://orcid.org/0000-0001-8758-2186)
- Alexander Kowar (ORCID: https://orcid.org/0000-0002-7868-3935)
- Helena Engel (ORCID: https://orcid.org/0000-0001-9792-7694)
- Ekaterina Stepanova (ORCID: https://orcid.org/0000-0002-4196-3191)
- Silvia Cadenas-De Miguel (ORCID: https://orcid.org/0000-0001-7611-589X)
- Ali Hyder Baig
- Cinthia Claudia Amaya Ramirez (ORCID: https://orcid.org/0009-0001-7669-5246)
- Giuliana Palazzo
- Ilaria Elia (ORCID: https://orcid.org/0000-0003-0922-9429)
- Beiping Miao (ORCID: https://orcid.org/0000-0003-2307-3280)
- Daniela Aviles-Huerta
- Victor M Cruz-Vilchez (ORCID: https://orcid.org/0009-0008-5269-4987)
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1038/s41467-025-59986-7
- Citations
- 1
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft
- Fonds Wetenschappelijk Onderzoek