Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling.

Authors

Déborah Suissa, Marine Fidelle, Ella Reich, Thao-Nguyen Pham, Simon Thomas, Johannes R Björk, Peng Liu, Liwei Zhao, Koji Kitaoka, Eléonore Piard, Isabelle Lebhar, Ai-Ling Tian, Cassandra Thelemaque, Carolina Alves Costa Silva, Eric Deutsch, Yohann Loriot, Nicola Segata, Gianmarco Piccinno, Geke A P Hospers, Saman Maleki Vareki, Michael S Silverman, John G Lenehan, Véronique Bataille, David Boulate, Tatiana Kuznetsova, Rinse K Weersma, Meriem Messaoudene, Sylvère Durand, Carlijn M van der Aalst, Harry J de Koning, Beatrice Schuler-Thurner, I Jolanda M de Vries, Edmond Rafie, Renée Maria Saliby, Marc Machaalani, Sebastian Haferkamp, Bastian Schilling, Serena Porcari, Chiara Ciccarese, Roberto Iacovelli, Chiara Cremolini, Toni K Choueiri, Arielle Elkrief, Guido Kroemer, Lucie Heinzerling, Kenji Chamoto, Gianluca Ianiro, Bertrand Routy, Lisa Derosa, Nikos Paragios, Laurence Zitvogel

Published in

Nature medicine. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.

PMID:
42350644
Bibliographic data and abstract were imported from PubMed on 26 Jun 2026.

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