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

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 Pechincha, Nora Siefert, Helena Engel, Shangce Du, Silvia Cadenas- De Miguel, Beiping Miao, Victor M. Cruz-Vilchez, Karin Müller-Decker, Ilaria Elia, Chong Sun, Wilhelm Palm and Fabricio Loayza-Puch ()
Additional contact information
Daniela Aviles-Huerta: German Cancer Research Center (DKFZ)
Rossella Del Pizzo: German Cancer Research Center (DKFZ)
Alexander Kowar: German Cancer Research Center (DKFZ)
Ali Hyder Baig: German Cancer Research Center (DKFZ)
Giuliana Palazzo: German Cancer Research Center (DKFZ)
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
Catarina Pechincha: University of Heidelberg
Nora Siefert: University of Heidelberg
Helena Engel: University of Heidelberg
Shangce Du: German Cancer Research Center (DKFZ)
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)

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59986-7

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