Aviles-Huerta Daniela, Del Pizzo Rossella, Kowar Alexander, Baig Ali Hyder, Palazzo Giuliana, Stepanova Ekaterina, Amaya Ramirez Cinthia Claudia, D'Agostino Sara, Ratto Edoardo, Pechincha Catarina, Siefert Nora, Engel Helena, Du Shangce, Cadenas-De Miguel Silvia, Miao Beiping, Cruz-Vilchez Victor M, Müller-Decker Karin, Elia Ilaria, Sun Chong, Palm Wilhelm, Loayza-Puch Fabricio
Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.
Nat Commun. 2025 May 19;16(1):4652. doi: 10.1038/s41467-025-59986-7.
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.
肿瘤微环境（TME）影响癌细胞的代谢和存活。然而，免疫细胞和基质细胞在体内如何应对代谢应激，以及营养限制如何影响治疗，目前仍知之甚少。在此，我们引入双核糖体分析（DualRP）来同时监测多个肿瘤细胞群体中的翻译和核糖体停滞情况。DualRP揭示，癌症-成纤维细胞相互作用会触发一种炎症程序，该程序可减少葡萄糖饥饿期间的氨基酸短缺。在具有免疫活性的小鼠中，我们发现丝氨酸和甘氨酸对最佳T细胞功能至关重要，而它们的缺乏会损害T细胞的健康状态。重要的是，免疫检查点阻断疗法会在T细胞中特别施加氨基酸限制，这表明不同疗法会在TME细胞类型中产生独特的代谢需求。通过以细胞类型特异性方式绘制密码子解析的核糖体停滞情况，DualRP揭示了塑造翻译程序的代谢串扰。因此，DualRP为剖析肿瘤细胞代谢相互作用和指导联合代谢免疫治疗策略提供了一种强大的创新方法。
