Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling

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. Mass-spectrometry-based metabolomic analysis of plasma samples from multiple cohorts of patients treated with immunotherapy across five distinct tumor types, followed by machine learning enabled identification of metabolic signatures, as well as functional exploration, reveals association of increased plasma histidine levels with prolonged survival and its potential for therapeutic intervention.

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Journal
Nature Medicine
Published
2026-06-25
DOI
https://doi.org/10.1038/s41591-026-04481-9
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
0.00

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article

Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling

Kenji Chamoto, Marine Fidelle, Véronique Bataille, Gianmarco Piccinno et al.
Nature Medicine
Cancer Immunotherapy and Biomarkers
article

Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling

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

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. Mass-spectrometry-based metabolomic analysis of plasma samples from multiple cohorts of patients treated with immunotherapy across five distinct tumor types, followed by machine learning enabled identification of metabolic signatures, as well as functional exploration, reveals association of increased plasma histidine levels with prolonged survival and its potential for therapeutic intervention.

Nature Medicine
Università Cattolica del Sacro Cuore (IT), University of Pisa (IT), Goethe University Frankfurt (DE), Western University (CA), Universidade Federal da Bahia (BR), Lawson Health Research Institute (CA), University Medical Center Groningen (NL), Harvard University (US), Radboud University Nijmegen (NL), Inserm (FR), University of Groningen (NL), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), King's College London (GB), University of Trento (IT), Université Paris Cité (FR), Aix-Marseille Université (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Erasmus MC (NL), Agostino Gemelli University Polyclinic (IT), Radboud University Medical Center (NL), LMU Klinikum (DE), University Hospital Regensburg (DE), Yale University (US), Sorbonne Université (FR), Universitätsklinikum Erlangen (DE), Centre de Recherche des Cordeliers (FR), Assistance Publique – Hôpitaux de Paris (FR), Hemel Hempstead Hospital (GB), Hôpital Européen Georges-Pompidou (FR), MedSIR (Spain) (ES), CentraleSupélec (FR), Mount Vernon Cancer Centre (GB), Hôpital Européen (FR), Immunité et Cancer (FR), Hôpital Nord (FR), Dana-Farber Cancer Institute (US), Hôpital Marie Lannelongue (FR), University Hospital Frankfurt (DE), Centre Hospitalier de l’Université de Montréal (CA), Center for Genomic Science (IT), St Joseph's Health Care (CA), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Azienda Ospedaliera Universitaria Pisana (IT), Fundação Oswaldo Cruz (BR), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), KU Leuven (BE)
Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Therakos, Regeneron Pharmaceuticals, Les Laboratories Pierre Fabre, Seerave Foundation, Astellas Pharma, Institut Gustave-Roussy, Servier, PharmaMar, Institut Servier, Genentech, EMD Serono, Janssen Pharmaceuticals, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 8%
Cancer Immunotherapy and Biomarkers
DOIOpen Access PDFOpenAlex
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